Anti-infectives from mangrove endophytic fungi

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Anti-infectives from mangrove endophytic fungi Sunil K. Deshmukha,*, Shivankar Agrawala,b, Ved Prakashc, Manish K. Guptaa, M. Sudhakara Reddyd a

TERI Deakin Nano Biotechnology Centre, The Energy and Resources Institute, Darbari Seth Block, IHC Complex, Lodhi Road, New Delhi 110003, India Indian Council of Medical Research (ICMR), IJMR Unit, V Ramalingaswami Bhawan, Ansari Nagar-AIIMS, Delhi 110029, India c Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, Uttar Pradesh, India d Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, Punjab 147004, India b

A R T I C L E

I N F O

Article History: Received 14 August 2019 Revised 2 January 2020 Accepted 2 January 2020 Available online xxx Keywords: Anti-infective activity Antimicrobial activity Mangrove endophytic fungi Secondary metabolites

A B S T R A C T

Endophytic fungi reside within the plant tissues and maintain a strong symbiotic relationship. They are of utmost importance as promising sources of chemically diverse bioactive natural products. These microbes alter gene expression levels, modulate biosynthetic pathways, mitigate stressful conditions in plants and thereby play an important role in establishing plant’s defence system against potential pathogens. The quest for discovering new chemical entities of pharmaceutical importance has drawn attention towards the mangrove ecosystem, which offers unique biodiversity. Mangroove associated fungi live under stress conditions and are the potential source of chemically diverse metabolites. Some fungal metabolites served as lead molecules for the development of new anti-infective agents. These fungi were modified/tailored using epigenetic means or culture optimization methods to improve the yield of useful metabolites. The present review describes the compounds isolated from mangrove endophytic fungi during 2013 2019 (up to June 2019) with focus on their chemical structure and their anti-infective activity. The compounds identified from endophytic fungi are arranged based on their antibacterial, antimycobacterial, antifungal, and antiviral activities. © 2020 SAAB. Published by Elsevier B.V. All rights reserved.

1. Introduction Mangroves flourish in coastal areas, estuaries of sub-tropical and tropical climates and mostly comprises of woody plants. Among the marine ecosystems, mangroves occupy second in terms of ecosystem habitat complexity, which include shrubs, ferns, palms, trees that are well acquainted with survival capability in fresh as well as the salt environment. They produce stilt roots that emerge out of the mud and help these plants to acquire oxygen and water required for survival. Mangroves are mainly tropical vegetation and are one of the most productive ecosystems (Kohlmeyer and Kohlmeyer, 1979; Volkmann-Kohlmeyer and Kohlmeyer, 1993; Shearer et al., 2007) and represent 9 orders, 20 families, 27 genera, and about 70 species. Mangrove vegetation covers a total area of 137,760 km2 (Alongi, 2002; Giri et al., 2011) and are reported to possess various medicinal properties (Salini, 2015; Das et al., 2015; Dahibhate et al., 2019). Endophytic fungi are those, which reside inside the plant tissue and spent one part of their lifecycle in plant system without causing any apparent pathogenic symptoms. Majority of endophytic fungi belong to ascomycetes, which is a polyphyletic group (Hyde and Soytong, 2008; Debbab et al., 2013). It is reported that higher plants may

* Corresponding author. E-mail address: [email protected] (S.K. Deshmukh).

harbour one or more endophytic fungi (Strobel et al., 2004). The interaction of the host plant with endophytic fungi may result in the production of diverse bioactive metabolites (Heinig et al., 2013). Endophytes are one of the significant group of mangrove fungi having a large number of bioactive compounds of pharmaceutical importance viz., antitumor, antibiotic, neuroprotective, antioxidant, anti-inflammatory, antiviral and immunomodulatory agents, etc. (Gunatilaka 2006; Kharwar et al., 2011; Imhoff, 2016; Deshmukh 2018, Deshmukh et al., 2015, 2018a, 2018b; Agrawal et al., 2019). Endophytes also function as plant growth promoters by producing phytohormones (Waqas et al., 2015), siderophores (Koulman et al., 2012), nitrogen fixation, solubilisation of minerals (Ngwene et al., 2016), ethylene suppression (Yuan et al., 2016) or via assisting phytoremediation (Li et al., 2012). The bioactive compounds produced from endophytic fungi of mangroves were reviewed by few authors (Xu, 2015; Alurappa et al., 2018). Amongst the marine fungi, mangrove fungi form the second largest group (Wang et al., 2014a) and produce bioactive compounds of various chemical classes such as terpenes, chromones, coumarins, polyketides, alkaloids, and peptides, etc. (Wang et al., 2014a; Deshmukh et al., 2018a, 2018b; Agrawal et al., 2019). The present review reports 106 novel compounds out of a total 183 compounds discovered during the period from 2013 to 2019 (Up to June) and were discussed based on their origin, chemical structure, and efficacies. The percent distribution of various anti-infective compounds isolated

https://doi.org/10.1016/j.sajb.2020.01.006 0254-6299/© 2020 SAAB. Published by Elsevier B.V. All rights reserved.

Please cite this article as: S.K. Deshmukh et al., Anti-infectives from mangrove endophytic fungi, South African Journal of Botany (2020), https://doi.org/10.1016/j.sajb.2020.01.006

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these are given in Table 2. The compounds discussed in the present review are listed based on their source of origin and the mode of action of the isolated compounds has described wherever possible. An attempt has been made to review the recent developments, such as co-cultivation and epigenetic modification for enhancing the production of secondary metabolites. 2. Antibacterial compounds 2.1. Compounds produced by coelomycetes

Fig. 1. Percentage distribution of bioactive metabolites reported during the period from 2013 to 2019 (Up to June) from mangrove endophytic fungi for various activities.

from mangrove endophytic fungi is reported in Fig. 1. The total number of compounds, as well as novel compounds isolated from mangrove fungi during the above mentioned period, is presented in Fig. 2. Novel anti-infective compounds identified from mangrove endophytic fungi are depicted in Table 1 and the chemical class of

A new isocoumarin derivative, pestalotiopisorin B (1) (Fig. 3), was extracted from endophytic fungus Pestalotiopsis sp., associated with Rhizophora stylosa, a mangrove plant collected from Dong Zhai Gang-Mangrove Garden on Hainan Island, China. The pestalotiopisorin B exhibited modest activity against Escherichia coli and Pseudomonas aeruginosa with MIC values of 12.5 and 50 mg/mL, respectively (Xu et al., 2018). A novel hybrid sesquiterpene-cyclopaldic acid metabolite with an unusual carbon skeleton, named Pestalotiopen A (2) (Fig. 3) was extracted from Pestalotiopsis sp., isolated from the leaves of the Rhizophora mucronata from the Dong Zhai Gang-Mangrove Garden on Hainan Island, China. A moderate activity against Enterococcus faecalis showing a MIC in range of 125 and 250 mg/mL has been reported with this compound (Hemberger et al., 2013). Oxysporone (3) possessing a 4H-furo(2,3-b)pyran-2 (3H)-one structure and xylitol (4) a five-carbon sugar alcohol (Fig. 3) was isolated from Pestalotia sp. associated with mangrove

Fig. 2. Novel bioactive compounds reported from mangrove endophytic fungi.

Please cite this article as: S.K. Deshmukh et al., Anti-infectives from mangrove endophytic fungi, South African Journal of Botany (2020), https://doi.org/10.1016/j.sajb.2020.01.006

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Sr. no.

Fungus

Host plant (s)

Plant part or tissue locality of host plants

Compounds isolated

Biological target

Biological active value (MIC/ IC50/ ID50)

Hainan Island, China

Pestalotiopisorin B (1)

MIC

Rhizophora mucronata Heritiera fomes

Leaves, Hainan Island, China Sundarbans, India

Pestalotiopen A (2)

Escherichia. coli and Pseudomonas aeruginosa Enterococcus faecalis

Antibacterial compounds Compounds produced by coelomycetes 1. Pestalotiopsis sp. Rhizophora stylosa Pestalotiopsis sp.

3.

Pestalotia sp.

4.

Phomopsis sp. HNY29-2B

Acanthus ilicifolius

Hainan Province, China

Acropyrone (5), ampelanol (6)

5.

Phomopsis longicolla

Brguiera sexangula var. rhynchopetala

Leaves, South China Sea

5,50 -dimethoxybiphenyl-2,20 -diol (7),

Compounds produced by ascomycetes 6. Ascomycota sp. Pluchea indica

7.

Guignardia sp.

Kandelia candel

Daya Bay, Shenzhen city, Guangdong province, China

Lasiodiplodia theobromae

Acanthus ilicifolius

Leaves

9.

Lasiodiplodia theobromae

Mangrove sediment

Dongzhai Harbor in Hainan, China

10.

Stemphylium sp.

Brguiera sexangula var. rhynchopetala

South China Sea

Methicillin-resistant Staphylococcus aureus strains, ATCC 25923, SA-1199B, RN4220, XU212, EMRSA-15, and EMRSA-16, Bacillus subtilis and P. aeruginosa S. aureus and B. subtilis Vibrio parahaemolyticus

Hemberger et al., 2013 Nurunnabi et al., 2018

MIC

5.60 and 11.21 mg/mL

Cai et al., 2017

MIC MIC

8.50 and 17.01 mg/mL 10 mg/mL

Li et al., 2017

2.5 and 5 mg/mL

Altersolanol B (8)

V. parahaemolyticus, and V. anguillarum

MIC

Dichlorodiaportintone (9), desmethyldichlorodiaportin (10), dichlorodiaportin (11)

MIC values in the range of 25 50 mg/mL

Chen et al., 2018

Guignardins B (12), C (13), BG1 (14)

S. aureus, B. subtilis, E. coli, Klebsiella pneumoniae, and Acinetobacter calcoaceticus S. aureus ATCC 29213

Ai et al., 2014

Guignardins B (12)

E. faecalis ATCC 29212

Palmarumycins BG1 (14)

Aeromonas hydrophila ATCC 7966

Chloropreussomerins A (15) and B (16), preussomerin H (17), preussomerin G (18), preussomerin F (19), preussomerin A (20) (+)-(R)-de-O-methyl-Lasiodiplodin (21)

S. aureus

Zones of inhibition 7, 8, and 8 mm (Tested at 50 mg/ disc) (Positive control penicillin 12 mm at the same level). Zone of inhibition of 7 mm (penicillin: 20 mm), at 50 mg/disc, Zone of inhibition of 12 mm (penicillin: 7 mm). at 50 mg/disc, MIC values between 1.6 and 13 mg/mL

Infectopyrones A (22)

Infectopyrones B (23) Ciprofloxacin

S. aureus ATCC 29,213, S. aureus ATCC 700,699 and E. faecium ATCC 35,667 Staphylococcus albus, and E. coli, B. subtilis, M. tetragenus, M. luteus

MIC

25 mg/ml

MIC 5.0 2.5 10.0 10.0 10.0 mg/ml

Chen et al., 2016

Umeokoli et al., 2019

Zhou et al., 2014

MIC 10.0, 2.5, >20.0, 10.0 and 10.0 mg/ml MIC 0.6, 0.3, 0.6, 0.3 and 0.3 mg/ml (continued on next page) 3

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8.

Oxysporone (3), xylitol (4)

MIC value between 125 and 250 mg/mL MIC values ranging from 32 to 128 mg/ml

Xu et al., 2018

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2.

12.5 and 50 mg/mL

References

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Please cite this article as: S.K. Deshmukh et al., Anti-infectives from mangrove endophytic fungi, South African Journal of Botany (2020),

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Table 1 Bioactive metabolites reported from Mangrove fungi.

Sr. no.

Fungus

Host plant (s)

Plant part or tissue locality of host plants

Compounds isolated

Biological target

Biological active value (MIC/ IC50/ ID50)

11.

Stemphylium sp. 33231

Brguiera sexangula var. rhynchopetala

South China Sea

Stemphol A (24), stemphol B (25), stemphol (26)

MIC

0.6 10 mg/ml

Zhou et al., 2015

12.

Hypocrea virens

Avicennia nitida

Branches

Viridiol (27)

S. aureus, E. coli, B. subtilis, M. tetragenus, K. rhizophila and B. cereus E. coli,

MIC

64 mg/mL

13.

Leptosphaerulina sp.

Excoecaria agallocha

Shankou in Guangxi province, China

Leptospyranonaphthazarin A (28), leptosnaphthoic acid A (29), diaportheins B (30) Leptosnaphthoic acid A (29)

Souza Sebastianes et al., 2017 Cui et al., 2017b

14. 15.

Talaromyces stipitatus

Acanthus ilicifolius

Mangrovederived rhizospheric soil Mangrove18. Eurotium derived rubrum rhizospheric MA-150 soil Compounds produced by hyphomycetes 19. Aspergillus Mangrovenidulans derived endophytic fungus

17.

Eurotium rubrum MA-150

K. peneumoniae and B. subtilis B. subtilis S. aureus and E. faecalis

MIC MIC

Benzofurans, (32 33)

S. aureus, S. epidermidis, E. coli, and B. subtilis

MIC values between 25 and 50 mg/mL

Talaromyones B (34)

B. subtilis

MIC

2-Benzofuran-1(3H)-one deriv. [(-) 1 and (+) 1] (35) and known analogs (36 37)

V. anguillarum

MIC 32, 64, and 64 mg/mL (Positive control, chloromycetin, MIC, 1.0 mg/mL)

Meng et al., 2016

Andaman Sea coastline, Thailand

Dihydroxyisoechinulin A (38)

V. alginolyticus

MIC 16.0 mg/mL (Positive control chloromycetin MIC 4.0 mg/mL)

Meng et al., 2015

Under 0.1% ethanol stress

Isoversicolorin C (39), versicolorin C (40)

E. coli, M. luteus, V. vulnificus, V. anguillarum, V. alginolyticus, Ed. ictaluri, V. parahaemolyticus S. aureus and B. subtilis

MIC value in the range of 1 64 mg/ml

Yang et al., 2018

MIC 8.0 and 0.25 mg/mL, showed the antibiofilm activity of penetration through the biofilm matrix and kills live bacteria inside mature S. aureus biofilm MIC values in the range of 0.33 21.6 mg/mL

Bai et al., 2014

Twig, Chanthaburi Province, Eastern Thailand Leaves, Zhanjiang Mangrove Nature Reserve in Guangdong Province, China Leaves Shankou Mangrove Nature Reserve in Guangxi Province, China Andaman Sea coastline, Thailand

Diaportheins B (30) Emodin (31)

Aspergillus flavipes

Acanthus ilicifolius

Shenzhen City, Guangdong Province, China

Flavipesin A (41)

21.

Aspergillus sp.

Unidentified mangrove plant

Hainan Island, China

Asperphenone A-B (42, 43)

22.

Aspergillus ochraceus

Bruguiera gymnorrhiza

Rhizospheric soil of marine mangrove plant, Hainan Island, China

Asperochrins A (44), Chlorohydroaspyrones A (45) and B (46), chlorohydroasperlactones A (47), penicillic acid (48), (R) 7-hydroxymellein (49)

S. aureus CMCC(B) 26,003, S. pyogenes ATCC19615, B. subtilis CICC 10,283 and M. luteus A. hydrophilia, V. anguillarum, and V. harveyi,

12.5 mg/mL

IC50 values ranging from 0.5 to 64.0 mg/mL

Zin et al., 2017 Chen et al., 2016

Cai et al., 2017

Guo et al., 2018

Liu et al., 2015

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20.

100 mg/ml 32 and 64 mg/mL

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Rhizophora mucronata Kandelia obovata

MIC 25.0, 50.0 and 50.0 mg/ml, MIC 100 mg/ml

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16.

Eurotium chevalieri Talaromyces amestolkiae

S. aureus

References

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Table 1 (Continued)

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Sr. no.

Fungus

Host plant (s)

Plant part or tissue locality of host plants

Compounds isolated

Biological target

Biological active value (MIC/ IC50/ ID50)

References

23.

Aspergillus sp.

Xylocarpus moluccensis

Leaves, Trang Province, Thailand

S. aureus ATCC 25,923

IC50 values ranging from 8.28 and 11.02 mg/mL

Wang et al., 2018

24.

Aspergillus niger

Avicennia marina

Hainan, China

(7S,10S) 7,10-epoxysydonic acid (50), (7R,11S) 7,12-epoxysydonic acid (51), 7-deoxy-7,14didehydro-12-hydroxysydonic acid (52), (E) 7-deoxy-7,8-didehydro-12-hydroxysydonic acid (53), engyodontiumone I (54), (+)-hydroxysydonic acid (55) and ( )-(7S) 10-hydroxysydonic acid (56) Malformins A1 (57) and C (58)

S. aureus

Liu et al., 2013

25.

Penicillium janthinellum

Mangrove rhizosphere soil

Penicilones B-D (59 61)

MRSA (S. aureus ATCC 43,300, ATCC 33,591)

26.

Penicillium citrinum

1-(2,6-dihydroxyphenyl)butan-1-one (62)

27.

Penicillium brocae

Brguiera sexangula var. rhynchopetala A. marina

Dongzhaigang mangrove natural reserve in Hainan Island, China South China Sea

Zone of inhibition of 9.0 and 8.5 mm diameter, (Positive control chloramphenicol 20.0 mm diameter) at a concentration of 20 mg/disk, MIC values ranging 3.13 6.25 mg/mL

B. subtilis, B. cereus and Micrococcus tetragenus E. coli, S. aureus, and Vibrio harveyi,

Spirobrocazines A, (63)

Spirobrocazines C (64) Brocazine G (65)

28. 29.

Penicillium brocae Penicillium citrinum

A. marina Bruguiera sexangula var. rhynchopetala

Fresh tissue, Hainan Island, China, South China Sea

Brocapyrrozin A (66), 4‑hydroxy‑3-phenyl-1Hpyrrol 2(5H)-one (67) Penicimarins G (68)

Penicimarin H (69), austinol (70) Penicimarin H (69) Austinol (70) Ciprofloxacin

Penicillium aculeatum

K. candel

Leaves, Yangjiang, Guangdong province, China

31.

Penicillium simplicissimum

Bruguiera sexangula var. rhynchopetala

Rhizosphere marine mangrove plant Hainan Island, China

(20 S*) 2-(20 -hydroxypropyl) 5-methyl-7,8dihydroxy-chromone (71), Bacillisporin A (72), bacillisporin B (73) Penicisimpins A-C (74,75,76)

S. aureus S. aureus, E. coli, Bacillus cereus, and V. alginolyticus S. epidermidis S. aureus, B. cereus, and V. alginolyticus B. cereus S. epidermidis, S. aureus, E. coli, B. cereus, and V. alginolyticus Salmonella sp.

Bacillus subtilis Aeromonas hydrophilia, E. coli, M. luteus, P. aeruginosa, V. alginolyticus, V. harveyi, and V. parahaemolyticus

MIC 32.0, 16.0, and 64.0 mg/mL, (Positive control chloromycetin, MIC 2.0, 0.5, and 2.0 mg/mL) MIC 32.0 mg/mL

Zheng et al., 2016

Meng et al., 2616a

MIC 0.25 mg/mL (Positive control, chloromycetin MIC = 0.5 mg/mL) MIC 0.125 and 0.5 mg/mL

Meng et al., 2017

5.6 mg/mL

Huang et al., 2016

MIC 2.78 mg/mL MIC of 5.56 mg/mL MIC of 9.17 mg/mL MIC 0.09, 0.09, 0.19, 0.39 and 0.414 mg/mL MIC

0.5 mg/mL

MIC 0.067 mg/mL MIC values ranging from 4 to > 64 mg/mL

Huang et al., 2017

Xu et al., 2016

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30.

E. coli, Aeromonas hydrophilia, and V. harveyi S. aureus

1.25 mg/mL

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Fresh tissue, Hainan Island, China

MIC

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Table 1 (Continued)

Sr. no.

Fungus

32.

Penicillium citrinum

33.

Penicillium citrinum

34.

Penicillium sp.

35.

Penicillium brocae

Compounds isolated

Biological target

Biological active value (MIC/ IC50/ ID50) MIC values ranging from 4 to > 64 mg/mL

South China Sea

20 -acetoxy-7-chlorocitreorosein (77)

Colletotrichum gloeosprioides and Phytophthora parasitica var. nicotianae Vibrio parahaemolyticus

MIC

3.76 mg/mL

He et al., 2017

South China Sea

Penibenzophenones A (78)

S. aureus

MIC

20 mg/mL

Zheng et al., 2018

2-Deoxy-sohirnone C (79)

Methicillin-resistant Staphylococcus aureus S. aureus

MIC

80 mg/mL

Jiang et al., 2018

Fresh tissue, Hainan Island, China

A. marina

Penicibrocazines B (80), C (81), D (82), congener (84)

Penicibrocazines C (81),

M. luteus

Penicibrocazines B (80), D (82), E (83), congener (84)

Gaeumannomyces graminis

Pyranonigrin F (85), and pyranonigrin A (86)

Staphyloccocus aureus, Vibrio harveyi and V. parahaemolyticus Alternaria brassicae and C. gloeosprioides

37.

Penicillium sp.

Bruguiera gymnorrhiza

MIC 32.0, 0.25, 8.0, and 0.25 mg/mL (Positive control, chloromycetin MIC, 4.0 mg/mL. MIC 0.25 mg/mL (Positive control, chloromycetin MIC = 2.0 mg/mL). MIC 0.25, 8.0, 0.25, and 64.0 mg/mL (positive control amphotericin B, MIC 16.0 mg/mL MIC 0.5 mg/mL (Positive control chloromycetin MICs 156 8.0, 2.0, and 128.0 mg/mL) MICs of 0.5 mg/ mL, (Positive control bleomycin MICs 32.0 and 4.0 mg/mL) MIC 8 mg/ml (Positive control, chloromycetin, MIC, 4 mg/ml) MIC 4.00 mg/mL

Iso-monodictyphenone (87)

Aeromonas hydrophilia

Acremonium Rhizophora strictum apiculate Alternaria Rhizophora tenuissima stylosa Anti-tuberculosis compounds Compounds produced by coelomycetes 39. Diaporthe sp. Acanthus ilicifolius

Island of Cat Ba, Vietnam

Cytosporone E (88)

S. aureus

Hainan Island in the South China Sea

Tricycloalternarene 3a (89), and djalonensone (90)

V. anguillarum

Zone of inhibition of 8 and 9 mm at 100 mg/disk

Branches, Shankou in Guangxi province, China

Diaporisoindole A (91), tenellone C (92)

IC50

40.

Nansha mangrove wetland, Guangdong province, China

Pestalol B (93)

Inhibitory activity against M. tuberculosis protein tyrosine phosphatase B (MptpB) Bioluminescence assay

38.

Pestalotiopsis sp.

Aegiceras corniculatum

1.77 and 2.2 mg/mL

Inhibitory activity against M. tuberculosis compared with dimethyl sulfoxide control with the INH (isoniazid) and RIF (rifampin) as positive drugs

Meng et al., 2015

Meng et al., 2015

Luo et al., 2014.

Hammerschmidt et al., 2014 Sun et al., 2013

Cui et al., 2017a

Sun et al., 2014

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Rhizospheric soil, Hainan Island, China

References

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Penicillium brocae

Bruguiera sexangula var. rhynchopetala Bruguiera sexangula var. rhynchopetala Bruguiera gymnorrhiza A. marina

Plant part or tissue locality of host plants

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36.

Host plant (s)

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Table 1 (Continued)

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Sr. no.

Fungus

Host plant (s)

Compounds produced by ascomycetes 41. Talaromyces sp. Kandelia obovata

Compounds produced by hyphomycetes 42. Aspergillus sp. Sonneratia apetala 43. Alternaria sp. Excoecaria agallocha 44. Penicillium Acanthus dipodomyicola ilicifolius 45. Aspergillus sp.

Compounds isolated

Biological target

Biological active value (MIC/ IC50/ ID50)

Huizhou Mangrove Nature Reserve in Guangdong Province, China

Talaramide A (94)

Inhibition of mycobacterial PknG activity

IC50

Leaves, Hainan Island, China Root Shankou, Guangxi Province, China Stem, Hainan Province, China South China Sea

(§)-Asperlone A (95), (§)-asperlone B (96) and (-)-mitorubrin (97) (+)-aS-Alterporriol C (98)

Inhibitory activity against MptpB Inhibitory activity against MptpB Inhibitory activity against MptpB Inhibitory activity against MptpB Kirby-Bauer disk diffusion susceptibility test (M. bovis BCG in 4 weeks-cultivated Middlebrook 7H11 agar plates) M. tuberculosis H37Ra

IC50 1.53, 1.63 and 1.52 mg/mL IC50 5.38 mg/mL

Peniphenone B (99), peniphenone C (100) Asperterpenoid A (101)

46.

Nigrospora sp.

K. andel

Decayed wood of collected from the South China Sea

4-Deoxybostrycin (102) and Nigrosporin (103)

47.

Mangrove fungus

Unidentified mangrove wood

Hat Khanom, Mu Ko Thale Tai National Park, Surat Thani province, Thailand

Palmarumycins P1 (104), decaspirones A (105),

Decaspirones C (106), palmarumycins CP3 (107) Anti-fungal compounds Compounds produced by coelomycetes 48. Phoma sp. Leizhou peninsula

Guangdong Province, China

Macrosporin (109)

7-(g ,g )-Dimethylallyloxymacrosporin (108), 7methoxymacrosporin (110) Altersolanol L (112)

Tetrahydroaltersolanol B (111) Carbendazim

Colletotrichum musae, C. gloeosporioides, Fusarium graminearum, Penicillium italicum, Fusarium oxysporum, f. sp. lycopersici, and Rhizoctonia solani

P. italicum, R. solani, F. graminearum and C. gloeosporioides P. italicum F. oxysporum F. graminearum C. musae, P. italicm R. solani C. gloeosporioides

18.2 mg/mL

References

Chen et al., 2017

Xiao et al., 2015 Xia et al., 2014

IC50 0.063 and 0.452 mg/ mL IC50 0.85 mg/mL

Li et al., 2014

Zone of inhibition zone size of 30 mm and 27 mm,

Wang et al., 2013a

MIC

1.56 mg/mL

MIC

3.13 mg/mL

MIC values ranging from 3.75 to 100 mg/mL

Huang et al., 2013

Bunyapaiboonsri et al., 2015

Huang et al., 2017

Average to poor (MICs 80 200 mg/mL) or no (MICs >200 mg/mL) MIC 35, 50, 100 and 200 mg/mL

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Plant part or tissue locality of host plants

S.K. Deshmukh et al. / South African Journal of Botany 00 (2020) 1 27

MIC 80 mg/mL. MIC 6.25, 6.25, 6.25, 3.125, 6.25, 12.5 mg/mL

(continued on next page)

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https://doi.org/10.1016/j.sajb.2020.01.006

Table 1 (Continued)

Sr. no.

Fungus

Host plant (s)

Plant part or tissue locality of host plants

Compounds isolated

Biological target

Biological active value (MIC/ IC50/ ID50)

49.

Phomopsis sp.

K. candel

Foliage, Fugong, Fujian, China

Diaporthelactone (113), 7‑hydroxy‑4,6-dimethy3H- isobenzofuran-1-one (114) 7-Methoxy-4,6-dimethyl-3H-isobenzofuran-1one (115) Ethyl 5-ethoxy-2-formyl-3‑hydroxy‑4-methylbenzoate (116)

A. niger

MIC

50 and 86.4 mg/mL

Alternaria alternaria

MIC

96.1 mg/mL

Fusarium graminearum, Gloeosporium musae, R. solani and Phytophthora sojae G. graminis, Rhizoctonia cerealis, Helminthosporium sativum and Fusarium graminearum

Zone of Inhibition 12.06, 11.57, 10.21, and 8.50 mm at 0.063 mg/mL

Wang et al., 2013b

MIC 220,160,130, and 250 mg/mL

Li et al., 2014a

50.

South China Sea coast

Phomopsis sp. and Alternaria sp. (coculture)

Cyclo-(L-leucyl-trans-4‑hydroxy‑L-prolyl-Dleucyl-trans-4‑hydroxy‑L-proline) (117)

Cyclo(d-Pro-L-Tyr-L-Pro-L-Tyr) (118)

C. albican, G. graminis, R.cerealis, H. sativum and F. graminearum

Cyclo (Gly-L-Phe-L-Pro-L-Tyr) (119) Ketoconazole Triadimefon

52.

South China Sea

Phomopsis sp. and Alternaria sp. (coculture)

(-)-Byssochlamic acid imide (120)

C. albican G. graminis, R. cerealis H. sativum and F. graminearum F. graminearum and F. oxysporum

Leaf, Leizhou Peninsula, China

Botryospyrones A (121), Botryospyrones B (122) Botryospyrones C (123) (3aS, 8aS) 1-acetyl-1, 2, 3, 3a, 8, 8a-hexahydropyrrolo [2,3b] indol-3a-ol (124) Triadimefon

54.

Guignardia sp.

K. candel.

Daya Bay, Shenzhen city, Guangdong province, China

Guignardins B (12), palmarumycins C1 (125), BG1 (14)

MIC 25,200,150, 200 and 250 mg/mL MIC 2 mg/mL MIC 150, 100, 120 and 150 mg/mL MIC 50 and 60 mg/mL

Ding et al., 2017

MIC 6.25 mg/mL

Carbendazim Compounds produced by ascomycetes 53. Botryosphaeria Myoporum ramosa bontioides

Huang et al., 2014

F. oxysporum F. graminearum F. oxysporum, P. italicum, and F. graminearum F. oxysporum, and F. graminearum F. oxysporum, P. italicum, and Fusarium graminearum F. oxysporum, P. italicum, and F. graminearum Fusarium sp.

F. oxysporum f. sp. niveum

Guignardins B (12), palmarumycins BG1 (14)

Aspergillus niger

Palmarumycins BG1 (14)

Fusarium oxysporum f. sp. cucumeris and R. solani

MIC 99.9, 2.99, and 149.9 mg/mL Zone of inhibition 6, 2, and 2 mm, at 25 mg/disc (positive control carbendazim 18 mm at the same level) Zones of inhibition 6 and 2 mm at 25 mg/disc (carbendazim 12 mm). Zones of inhibition 7 and 4 mm at 25 mg/disc (carbendazim: 10 mm). Zones of inhibition 2 and 2 mm at 25 mg/disc (carbendazim: 12 and 14 mm), respectively

Wu et al., 2019

Ai et al., 2014

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Palmarumycins C1 (125), BG1 (14)

MIC 25.11 and 200.75 mg/ mL MIC 25.0, 50.18 and 50.18 mg/mL MIC 50.1 mg/mL against both the pathogens MIC 6.26, 12.5 and 6.26 mg/mL

ARTICLE IN PRESS

Phomopsis sp. and Alternaria sp. (coculture)

Zhang et al., 2014

S.K. Deshmukh et al. / South African Journal of Botany 00 (2020) 1 27

51.

MIC 150 100, 120, and 150 mg/mL MIC 35, 300, 250, 350 and 400 mg/mL

References

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8

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Table 1 (Continued)

JID: SAJB

Sr. no.

Fungus

Host plant (s)

Compounds produced by hyphomycetes 55. Fusarium sp. Myoporum bontioides

Plant part or tissue locality of host plants

Compounds isolated

Biological target

Biological active value (MIC/ IC50/ ID50)

Leizhou Peninsula, China

Fusarihexin A (126)

Colletotrichum gloeosporioides, C. musae, Fusarium oxysporum Schlecht. f. sp. lycopersici

MIC

Fusarihexin B (127), Cyclo(L-Leu-L-Leu-D-Leu-L-Leu-L-Val) (128) Carbendazim Aspergillus fumigatus

Acrostichum specioum

Hainan island

Spiculisporic acid B (129)

C. albicans

57.

Aspergillus clavatus

Myoporum bontioides

Root, Leizhou Peninsula, China

4,40 -dimethoxy-5,50 -dimethyl-7,70 -oxydicoumarin (130), (S) 5‑hydroxy‑2,6-dimethyl-4Hfuro[3,4-g]benzopyran-4,8(6H)-dione (131), 24-hydroxylergosta-4,6,8(14),22-tetraen-3one (132), kotanin (133), orlandin (134) Compound (132)

F. oxysporum, C. musae, and P. italicum

Compounds (130, 133, and 134)

F. oxysporum

Compound (131) Triadimefon

C. musae, F. oxysporum, C. musae and P. italicm Fusarium graminearum

58.

Alternaria sp.

Myoporum bontioides

Root, Leizhou peninsula, Guangdong Province, China

59.

Penicillium chrysogenum

M. bontioides

Vein, South China

(§)-(4S*,5S*) 2,4,5-trihydroxy-3‑methoxy‑4methoxycarbonyl-5-methyl-2-cyclopenten-1one (135), 4‑chloro‑1,5-dihydroxy-3-hydroxymethyl-6-methoxycarbonyl-xanthen-9-one (136) Compound (136) Penochalasin I (137),

MIC 12.3, 12.3 and 24.7 mg/mL MIC 50.2, 24.85 and 12.7 mg/mL MIC 12.4, 6.3, and 6.3 mg/ mL Zones of inhibition 8.6 mm (Positive control ketoconazole with zone of inhibition 29.2 mm) at the concentration of 20 mg/ mL, MIC in the range of 24.37 240.25 mg/mL

MIC 10.12, 80.13 and 25.04 mg/mL MIC 100.28, 103.4, and 103.58 mg/mL MIC 54.70 mg/mL MIC 99.9, 80.0, and 49.9 mg/mL MIC 54.95, and 37.39 mg/ mL

74.78 mg/mL 100.46 mg/mL

MIC MIC

Penochalasin J (138), chaetoglobosins F, (139), C, (140) A, (141), E, (142) and armochaetoglobosin I (143) Compounds (140 143)

C. musae, C. gloeosporioides, P. italicum, and R. solani. R. solani

MIC values ranging from 24.20 53.24 mg/mL

Compounds (140, 142, 138)

C. gloeosporioides

Guo et al., 2017

Li et al., 2017

Wang et al., 2015

Huang et al., 2016

MIC 12.50, 6.25, 6.25, and 5.96 mg/mL (Positive control carbendazim MIC 6.24 mg/mL MIC 25.0, and 12.51,12.50, mg/mL (Positive control carbendazim MIC 12.49 mg/mL). (continued on next page)

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Calletotrichum musae R. solani

Zhu et al., 2018

ARTICLE IN PRESS

56.

14, 29 and 14 mM,

References

S.K. Deshmukh et al. / South African Journal of Botany 00 (2020) 1 27

Please cite this article as: S.K. Deshmukh et al., Anti-infectives from mangrove endophytic fungi, South African Journal of Botany (2020),

https://doi.org/10.1016/j.sajb.2020.01.006

Table 1 (Continued)

Sr. no.

Fungus

Host plant (s)

Plant part or tissue locality of host plants

Compounds isolated

Biological target

Biological active value (MIC/ IC50/ ID50)

References

60.

Penicillium chrysogenum

M. bontioides

Vein, South China

Penochalasin K (144)

C. gloeosporioides and R. solani

Zhu et al., 2017

61.

Penicillium sp.

(Z) 7,40 -dimethoxy-6‑hydroxy‑aurone-4-Ob-glucopyranoside (145)

62. 63.

Penicillium bilaiae Penicillium brocae

Candida sp. (Candida krusei ATCC62578, C. krusei CK5 C. albicans ATCC18804, C. albicans CA12, C. glabrata ATCC90030, C. glabrata CG5, C. parapsilosis ATCC 22014, C. tropicalis ATCC 13803 C. tropicalis CT2) C. gloeosporioides Alternaria brassicae and C. gloeosprioides

MICs 3.13 and 6.26 mg/mL (Positive control Carbendazim MIC of 12.49 and 6.24 mg/mL). MIC in the range of 1.5 2.5. mg/mL

Anti- viral compounds Compounds produced by coelomycetes 65. Pestalotiopsis sp. Aegiceras corniculatum

66. 67.

Pestalotiopsis vaccinii Pestalotiopsis vaccinii

Penicibilaenes A (146) and B (147) Pyranonigrin F (148), pyranonigrin A (149)

Leaf Songkhla province, Thailand

Tremulenolide A (150)

Cryptococcus neoformans ATCC90113 S. aureus

MIC

Inner stems, Nansha mangrove wetland, Guangdong province, China

Pestalols A (151), B (94) C-E (152 154), Transharzialactones A (155), F (156), 3b, 5a, 9a-trihydroxy-7, 22-en-ergost-6-one (157) and 3b-‑hydroxy‑sterol (158) Compound (158)

A/HK/8/68 (H3N2) virus and A/ WSN/33 (H1N1)

Potency to different extents

IC50

1.93 and 0.90 mg/ mL

IC50

3.88 mg/mL

Southern China

Vaccinal A (159)

K. candel

Southern China

Vaccinols J (160)

EV71

IC50 8.36 mg/mL and the inhibition effect was stronger than positive control ribavirin (IC50 43.22 mg/mL)

Wang et al., 2017

Neosartoryadins A (161) and B (162)

H1N1

IC50 32.11 and 29.14 mg/ mL (Positive control ribavirin, IC50 22.95 mg/mL)

Yu et al., 2015

Trichodimerol (163)

NA (H7N9)/MUNANA model

IC50

37.03 mg/mL

Oxoglyantrypine (164), norquinadoline A (165), deoxynortryptoquivaline (166), deoxytryptoquivaline (167), tryptoquivaline (168) and quinadoline B (169) Isoaspulvinone E (170), aspulvinone E (171), pulvic acid (172) Compound (170)

H1N1

IC50

29.27

Aspergillus terreus

H1N1

IC50 32.3, 56.9, and 29.1 mg/mL IC50 62.14 mg/mL

Leaves, stems and peels, Hainan province of China Guangzhou, China

Rhizosphere soil, coast of Fujian province, China

Compounds (170 171)

Inhibitory activity against H1N1 viral neuraminidase (NA), Docking into the active sites of NA

39.11 mg/mL

Wang et al., 2014

Zhang et al., 2014

Peng et al., 2013

Gao et al., 2013

E double bond D5(10) was essential to achieve activity (continued on next page)

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71.

Sun et al., 2014

K.candel

Compounds produced by hyphomycetes 69. Trichoderma sp. Xylocarpus granatum

Cladosporium sp.

Klaiklay et al., 2013

A/HK/8/68 (H3N2), A/ WSN/33 (H1N1) EV71

Compounds produced by ascomycetes 68. Neosartorya udagawae

70.

128 mg/mL

Meng et al., 2014 Meng et al., 2015

ARTICLE IN PRESS

Compounds produced by basidiomycoycetes 64. Flavodon flavus Rhizophora apiculata

MIC 1.0 and 0.125 mg/mL MICs 0.5 mg/ mL (Positive control bleomycin, MICs 32.0 and 4.0 mg/mL)

Rhizospheric soil

Song et al., 2015

S.K. Deshmukh et al. / South African Journal of Botany 00 (2020) 1 27

Lumnitzera racemosa A. marina

JID: SAJB

10

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Table 1 (Continued)

ARTICLE IN PRESS

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HCV, HBV

Brefeldin E1 E5 (174 178) and alternariol-5-Omethyl ether, (181), 30 -hydroxyalternariol-5O-methyl ether (182), mangrovamides A (183) Brefeldin A (179), brefeldin A 7-O-acetate (180),

HCV, HBV

ID50 value ranging from 4.03 mg/mL to 7.09 mg/mL

Xie et al., 2017

Li et al., 2018

IC50 0.003 mg/mL (Positive control oseltamivir IC50 0.00099 mg/mL Poor antiviral activity Influenza neuraminidase Simpterpenoid A (I) (173)

Penicillium sp. 73.

Panax notoginseng

Penicillium simplicissimum 72.

Bruguiera sexangula var. rhynchopetala

Rhizospheric soil, Hainan island in the South China Root Wenshan, Yunnan province of China

Biological target Fungus Sr. no.

Table 1 (Continued)

Host plant (s)

Plant part or tissue locality of host plants

Compounds isolated

Biological active value (MIC/ IC50/ ID50)

References

S.K. Deshmukh et al. / South African Journal of Botany 00 (2020) 1 27

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plant Heritiera fomes from Sundarbans region. These compounds displayed activity against Methicillin-resistant Staphylococcus aureus (MRSA) resistant strains ATCC 25,923, EMRSA-15, EMRSA-16, RN4220, SA-1199B, and XU212 with MIC values ranging from 32 to 128 mg/mL (Nurunnabi et al., 2018). Two known compounds acropyrone (5) and ampelanol (6) (Fig. 3) were isolated from the endophytic fungus Phomopsis sp. HNY29-2B associated with Acanthus ilicifolius, which was collected from the South China Sea in Hainan Province, China. Acropyrone exhibited antibacterial activity against Bacillus subtilis and P. aeruginosa with MIC values of 5.60 and 11.21 mg/mL, respectively and ampelanol (6) exhibited activity against S. aureus and B. subtilis with MIC values of 8.50 and 17.01 mg/mL, respectively (Cai et al., 2017). A new biphenyl derivative 5,50 -dimethoxybiphenyl-2,20 -diol (7), and a known compound altersolanol B (8) (Fig. 3) were isolated from Phomopsis longicolla HL-2232 inhabiting leaves of Brguiera sexangula var. rhynchopetala collected in the South China Sea. 5,50 -dimethoxybiphenyl-2,20 -diol (7) exhibited moderate antimicrobial activity against Vibrio parahaemolyticus with a MIC value of 10 mg/mL and altersolanol B (8) showed inhibitory effects on V. parahaemolyticus and Vibrio anguillarum with MIC values of 2.5 and 5 mg/mL, respectively (Li et al., 2017). 2.2. Compounds produced by ascomycetes A new isocoumarin, dichlorodiaportintone (9), and two known compounds desmethyl-dichlorodiaportin (10) and dichlorodiaportin (11) (Fig. 3) were extracted from the culture of Ascomycota sp. CYSK-4 obtained from Pluchea indica. These compounds exhibited antibacterial activity against S. aureus, B. subtilis, E. coli, Klebsiella pneumoniae, and Acinetobacter calcoaceticus with the MIC values ranging from 25 50 mg/mL (Chen et al., 2018). Guignardins B (12), C (13), new spirodioxynaphthalenes along with known analogue palmarumycin BG1 (14) (Fig. 3) were isolated from Guignardia sp. KcF8 inhabiting a mangrove plant Kandelia candel collected from Guangdong province, China. At a concentration of 50 mg/disc, compounds Guignardins B (12), C (13) and palmarumycin BG1(14) exhibited zone of inhibition of 7, 8, and 8 mm against S. aureus ATCC 29213, whereas positive control penicillin displayed a zone of 12 mm at the same level. Similarly, at a concentration of 50 mg/disc, Guignardins B exhibited inhibition of 7 mm (penicillin: 20 mm) against Enterococcus faecalis ATCC 29212. The palmarumycin BG1 exhibited a zone of inhibition of 12 mm against Aeromonas hydrophila ATCC 7966 at a concentration of 50 mg/disc, while the positive control penicillin exhibited 7 mm zone of inhibition (Ai et al., 2014). Two novel chlorinated preussomerins, chloropreussomerins A (15) and B (16), and other previously identified compounds, preussomerin H (17), preussomerin G (18), preussomerin F (19), and preussomerin A (20) (Fig. 3) were isolated from Lasiodiplodia theobromae ZJ-HQ1, an endophytic fungus from the leaves of Acanthus ilicifolius. These compounds displayed antibacterial activity against S. aureus with MIC value in the range of 1.6 and 13 mg/mL (Chen et al., 2016). A known compound (+)-(R)-de-O-methyl-lasiodiplodin (21) (Fig. 3), was obtained from Lasiodiplodia theobromae M4.2-2 isolated from sediment of mangrove region collected at Dongzhai Harbor in Hainan, China exhibited activity against S. aureus ATCC 29213, S. aureus ATCC 700699, and E. faecium ATCC 35667 with MIC values of 25 mg/mL (Umeokoli et al., 2019). Two new a-pyrone derivatives, infectopyrones A (22) and B (23) (Fig. 3) were isolated from Brguiera sexangula var. rhynchopetala inhabiting Stemphylium sp. 33231 collected in the South China Sea. Infectopyrone A (22) showed significant activity against Staphylococcus albus, E. coli, B. subtilis, M. tetragenus and M. luteus with MIC values of 5.0, 2.5, 10.0, 10.0, 10.0 mg/mL, respectively. The infectopyrone B (23) had shown little weaker activity than infectopyrone A (22) against S. albus, E. coli, B. subtilis, M. tetragenus, and M. luteus, with MIC values of 10.0, 2.5, 20.0, 10.0 and 10.0 mg/ml, respectively. While

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S.K. Deshmukh et al. / South African Journal of Botany 00 (2020) 1 27 Table 2 Chemical classes of various metabolite reported from Endophytic Fungi. Fungal species Coelomycetes Pestalotiopsis sp. Pestalotiopsis sp. Pestalotia sp Phomopsis sp. Phomopsis longicolla Diaporthe sp. SYSU-HQ3 Pestalotiopsis sp. AcBC2 Phoma sp. L28 Phomopsis sp. A123 Phomopsis sp. K38 and Alternaria sp. E33 Phomopsis sp. K38 and Alternaria sp. E33. Fungi strain Nos. K38 and E33 Pestalotiopsis sp. AcBC2 Pestalotiopsis sp. AcBC2 Pestalotiopsis vaccinii (cgmcc3.9199) Pestalotiopsis vaccinii (cgmcc3.9199) Ascomycetes Ascomycota sp. Guignardia sp. Lasiodiplodia theobromae ZJ-HQ1 Brguierasexangula var. rhynchopetala Stemphylium sp. 33231 Hypocrea virens Leptosphaerulina sp. SKS032 Leptosphaerulina sp. SKS032 Eurotium chevalieri KUFA 0006 Talaromyces amestolkiae YX1 Talaromyces stipitatus SK-4 Eurotium rubrum MA-150 Eurotium rubrum MA-150 Botryosphaeria ramosa L29 Hyphomycetes Aspergillus nidulans MA-143 Aspergillus flavipes AIL8 Aspergillus sp. YHZ-1 Aspergillus ochraceus MA-15 Aspergillus sp. xy02 Aspergillus niger MA-132 Penicillium janthinellum HK1-6 Penicillium brocae MA-231 Penicillium brocae MA-231 Penicillium citrinum Penicillium aculeatum (No. 9EB) Penicillium simplicissimum MA-332 Penicillium sp. GD6 Penicillium brocae MA-231 Penicillium sp. MA-37 Aspergillus sp. 16-5C Alternaria sp. (SK11) Aspergillus sp. Nigrospora sp. Fungus BCC 25093 Fusarium sp. R5 Aspergillus clavatus No. R7 Aspergillus clavatus No. R7 Aspergillus clavatus No. R7 Aspergillus clavatus No. R7 Alternaria sp. R6 Alternaria sp. R6 Penicillium chrysogenum V11 Penicillium chrysogenum V11 Penicillium sp.FJ-1 Penicillium bilaiae MA-267 Penicillium brocae MA-231 Cladosporium sp. PJX-41 Cladosporium sp. PJX-41 Aspergillus terreus Gwq-48

Chemical class

Comp.

References

Isocoumarin Cyclopaldic acid Oxysporone Oxysporone Biphenyls Isoprenylisoindole Benzaldehyde der. Anthraquinone Isobenzofuranone Benzaldehyde der. Cyclic tetrapeptide Nonadride der. Alkenyl phenol der. Alkenyl benzaldehyde der. Naphthalene der. Salicyloid der.

1 2 3, 4 5, 6 7, 8 91 93 108 113 116 117 120 151, 152 159 160

Xu et al., 2018 Hemberger et al., 2013 Nurunnabi et al., 2018 Cai et al., 2017 Li et al., 2017 Cui et al., 2017a Sun et al., 2014 Huang et al., 2017 Zhang et al., 2014 Wang et al., 2013b Li et al., 2014a; Huang et al., 2014 Ding et al., 2017 Sun et al., 2014 Sun et al., 2014 Sun et al., 2013 Wang et al., 2017

Isocoumarin Spirodioxynaphthalenes Preussomerins A-pyrone Stemphol sulfate Steroid Naphthazarin 2- naphthoic acid Anthraquinone Benzofuran Depsidone 2-benzofuran-1(3H)-one Indolediketopiperazine Isocoumarin

9 11 12 14 15 21 22, 23 24 26 27 28 29 31 32, 33 34 35, 36 38 121 123

Chen et al., 2018 Ai et al., 2014 Umeokoli et al., 2019 Zhou et al., 2014 Zhou et al., 2015 Souza Sebastianes et al., 2017 Cui et al., 2017b Cui et al., 2017b Zin et al., 2017 Chen et al., 2016 Cai et al., 2017 Meng et al., 2016 Meng et al., 2015 Wu et al., 2019

Anthraquinone Butyrolactone Phenone der. Polyketide Phenolic bisabolanesesquiterpenoid Cyclopentapeptide Azaphilone Diketopiperazine Phenopyrrozin der. Dihydroxycoumarin Chromone der. Dihydroisocoumarin der. Sorbicillin der. Sulfide diketopiperazine der. Benzophenone der. Dinaphthalenone der. Anthraquinone der. Sesterterpenoid Anthraquinone Spirodioxynaphthalene Cyclic hexadepsipeptide Coumarin der. Chromone der. Sterone der. Bicoumarin Cyclopentenone der. Cyclohexenone der. Cheatoglobosin Chaetoglobosin Glucopyranoside der. Sesquiterpene Pyrrole der. Indole der. Pyrazinoquinazoline der. Butenolide der.

39, 40 41 42, 43 44 50 56 57, 58 59 61 63 65 66, 67 68, 69 71 74 76 79 80 84 87 95, 96 98 101 102 104 107 126, 127 130 131 132 133 134 135 136 137 143 144 145 146, 147 148, 149 164 165 170 172

Yang et al., 2018 Bai et al., 2014 Guo et al., 2018 Liu et al., 2015 Wang et al., 2018 Liu et al., 2013 Chen et al., 2017 Meng et al., 2016 Meng et al., 2017 Huang et al., 2016 Huang et al., 2017 Xu et al., 2016 Jiang et al., 2018 Meng et al., 2015 Luo et al., 2014 Xiao et al., 2015 Xia et al., 2014 Huang et al., 2013 Wang et al., 2013a Bunyapaiboonsri et al., 2015 Zhu et al., 2018 Li et al., 2017 Li et al., 2017 Li et al., 2017 Li et al., 2017 Wang et al., 2015 Wang et al., 2015 Huang et al., 2016 Zhu et al., 2017 Song et al., 2015 Meng et al., 2014 Meng et al., 2015 Peng et al., 2013 Peng et al., 2013 Gao et al., 2013

ciprofloxacin showed the antibacterial activity against S. albus, E. coli, B. subtilis, M. tetragenus, and M. luteus with MIC values of 0.6, 0.3, 0.6, 0.3 and 0.3 mg/mL, respectively (Zhou et al., 2014).

111 115 119

154

Two new stemphol sulfates, stemphol A (24) and stemphol B (25) along with previously identified compound stemphol (26) (Fig. 3), were isolated from the endophytic Stemphylium sp. 33231. These stemphols exhibited antibacterial activities against S. aureus, E. coli, B.

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Fig. 3. Structures of metabolites isolated from mangrove endophytic fungi with antibacterial activity (1 28).

subtilis, M. tetragenus, K. rhizophila and B. cereus with MIC values ranging from 0.6 to 10 mg/mL (Zhou et al., 2015). Viridiol (27) (Fig. 3) a steroidal phytotoxin was obtained from endophytic fungus Hypocrea virens associated with Avicennia nitida exhibited antibacterial activity against E. coli, with a MIC of 64 mg/mL (Souza Sebastianes et al., 2017).

Two new compounds, leptospyranonaphthazarin A (28) (Fig. 3) and leptosnaphthoic acid A (29), together with a known compound, diaporthein B (30) (Fig. 4) were isolated from an endophytic fungus Leptosphaerulina sp. SKS032 associated with Excoecaria agallocha collected from Guangxi province, China. These compounds exhibited antibacterial activities against S. aureus with MIC values of 25.0, 50.0 and

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S.K. Deshmukh et al. / South African Journal of Botany 00 (2020) 1 27

Fig. 4. Structures of metabolites isolated from mangrove endophytic fungi with antibacterial activity (29 53).

50.0 mg/mL, respectively. Leptosnaphthoic acid A (29) also exhibited weak antibacterial activities against K. peneumoniae and B. subtilis at the concentration of 100 mg/mL. Diaporthein B (30) exhibited weak antibacterial activities against B. subtilis at the concentration of 100 mg/mL (Cui et al., 2017b). Previously described anthraquinone,

emodin (31) (Fig. 4) was isolated from the endophytic fungus Eurotium chevalieri KUFA 0006 associated with Rhizophora mucronata Poir collected from Chanthaburi Province, Eastern Thailand. Emodin (31) exhibited antibacterial activity against S. aureus and E. faecalis with MIC values of 32 and 64 mg/mL, respectively (Zin et al., 2017).

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Two new benzofurans, (32, 33) (Fig. 4) were isolated from the endophytic fungus Talaromyces amestolkiae YX1 associated with Kandelia obovate collected from the Guangdong Province, China. These benzofurans displayed activity against S. aureus, S. epidermidis, E. coli, and B. subtilis with the MIC values between 25 and 50 mg/mL (Chen et al., 2016). A new depsidone, talaromyone B (34) (Fig. 4) was isolated from endophytic fungus Talaromyces stipitatus SK-4 obtained from the leaves of a mangrove plant Acanthus ilicifolius collected from Shankou Mangrove Nature Reserve in Guangxi Province, China. Talaromyone B (34) showed antibacterial activity against B. subtilis with a MIC value of 12.5 mg/mL (Cai et al., 2017). Enantiomers of a 2-benzofuran-1(3H)-one derivative, [( )-1 and (+)-1] (35) and known analogs (36, 37) (Fig. 4), were extracted from the culture of Eurotium rubrum MA-150, associated with mangrove-derived rhizospheric soil, collected from the Andaman Sea coastline, Thailand. These compounds exhibited weak activities against V. anguillarum with MIC values of 32, 64, and 64 mg/mL, respectively, while chloromycetin, a positive control showed MIC of 1.0 mg/mL (Meng et al., 2016). A known indolediketopiperazine alkaloid analogue, dihydroxyisoechinulin A (38) (Fig. 4) was also isolated from Eurotium rubrum MA-150. This compound (38) showed activity against Vibrio alginolyticus with a MIC of 16.0 mg/ mL, while the MIC for the positive control, chloromycetin was 4.0 mg/ mL) (Meng et al., 2015). 2.3. Compounds produced by hyphomycetes A new anthraquinone derivative isoversicolorin C (39), and a related metabolite versicolorin C (40) (Fig. 4) were isolated from the mangrove associated fungus Aspergillus nidulans MA-143 under 0.1% ethanol stress. Isoversicolorin C (39) and versicolorin C (40) displayed potent antibacterial activity against E. coli, M. luteus, V. vulnificus, V. anguillarum, V. alginolyticus, Ed. ictaluri, and V. parahaemolyticus with MIC ranging between 1 and 64 mg/mL (Yang et al., 2018). New aromatic butyrolactones, flavipesin A (41) (Fig. 4) was isolated from Aspergillus flavipes AIL8 associated with Acanthus ilicifolius collected from Guangdong Province, China. Flavipesin A (41) showed week antibacterial activity against S. aureus and B. subtilis with MIC values of 8.0 and 0.25 mg/mL, respectively. It also exhibited antibiofilm activity that showed potential to kill live bacteria present inside mature S. aureus biofilm (Bai et al., 2014). Two new phenone derivatives, asperphenone A and B (42, 43) (Fig. 4), were isolated from Aspergillus sp. YHZ-1 inhabiting unknown mangrove plants from Hainan Island, China. Asperphenone A (42) and B (43) exhibited mild activity against four Gram-positive bacteria, S. aureus CMCC(B) 26003, S. pyogenes ATCC19615, B. subtilis CICC 10283 and M. luteus with the MIC values in the range of 0.33 21.6 mg/mL (Guo et al., 2018). A new polyketides asperochrin A (44), along with known related derivatives, chlorohydroaspyrones A (45) and B (46), chlorohydroasperlactones A (47), penicillic acid (48) and (R)-7-hydroxymellein (49) (Fig. 4) were isolated from Aspergillus ochraceus MA-15, from the rhizospheric soil of marine mangrove plant Bruguiera gymnorrhiza collected from Hainan Island, China. These compounds displayed selective antibacterial activity against A. hydrophilia, V. anguillarum, and V. harveyi, with IC50 values ranging from 0.5 to 64.0 mg/mL (Liu et al., 2015). New phenolic bisabolanesesquiterpenoids, (7S,10S)-7,10-epoxysydonic acid (50), (7R,11S)-7,12-epoxysydonic acid (51), 7-deoxy-7,14didehydro-12-hydroxysydonic acid (52), and (E)-7-deoxy-7,8-didehydro12-hydroxysydonic acid (53) (Fig. 4), along with known analogs engyodontiumone I (54), (+)-hydroxysydonic acid (55) and ( )-(7S)-10hydroxysydonic acid (56) (Fig. 5), were isolated from Aspergillus sp. xy02 associated with Xylocarpus moluccensis collected in Trang Province, Thailand. These compounds (50 56) exhibited moderate inhibitory activity against S. aureus ATCC 25923 with IC50 values ranging from 8.28 and 11.02 mg/mL (Wang et al., 2018). Two known cyclopentapeptides, malformins A1 (57) and C (58) (Fig. 5), were isolated from Aspergillus niger MA-132, an endophytic

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fungus associated with Avicennia marina collected in Hainan, China. Malformins A1 (57) and C (58) exhibited weak antibacterial activities against S. aureus with a clear inhibition zone of 9.0 and 8.5 mm diameter, respectively, at a concentration of 20 mg/disk, while chloramphenicol showed a 20.0 mm diameter of inhibition zone at the same concentration (Liu et al., 2013). New azaphilones, penicilones B, C and D (59 61) (Fig. 5), were isolated from Penicillium janthinellum HK1-6 from the mangrove rhizosphere soil, collected from Dongzhaigang mangrove natural reserve in Hainan Island, China. These compounds showed potent anti-MRSA (S. aureus ATCC 43300, ATCC 33591) activities with MIC values ranging from 3.13 6.25 mg/mL (Chen et al., 2017). A known compound 1-(2,6-dihydroxyphenyl) butan-1-one (62) (Fig. 5) isolated from the endophytic fungus Penicillium citrinum HL-5126 inhabiting inside Brguiera sexangula var. rhynchopetala collected from the South China Sea exhibited strong inhibitory potential against B. subtilis, B. cereus, and Micrococcus tetragenus with MIC value of 1.25 mg/mL (Zheng et al., 2016). New diketopiperazines, spirobrocazines A and C (63 64) and brocazine G (65) (Fig. 5) were isolated from Penicillium brocae MA-231 associated with A. marina collected at Hainan Island, China. The above compounds were isolated using one strain many compounds (OSMAC) approach. Brocazine G (65) showed activity against S. aureus showing MIC value of 0.25 mg/mL, while chloromycetin, a positive control gave MIC of 0.5 mg/mL. Against S. aureus, E. coli, and Vibrio harveyi, spirobrocazine A (63) showed MIC values of 16.0, 32.0, and 64.0 mg/mL, respectively. Spirobrocazine C (64) showed activity against E. coli, Aeromonas hydrophilia, and V. harveyi with identical MIC value of 32.0 mg/mL (Meng et al., 2016). Two new N-containing p-hydroxyphenopyrrozin derivatives brocapyrrozin A (66) and 4‑hydroxy‑3-phenyl-1H-pyrrol 2 (5H)-one (67) (Fig. 5) were obtained using OSMAC approach from Penicillium brocae MA-231 associated with A. marina. Both these compounds showed potent activity against S. aureus with MIC values of 0.125 and 0.5 mg/mL, respectively (Meng et al., 2017). Two new dihydroxycoumarin penicimarins G and H (68, 69) and austinol (70) (Fig. 5) were isolated from mangrove Bruguiera sexangula var. rhynchopetala inhabiting Penicillium citrinum collected from the South China Sea. Penicimarin G (68) displayed the same MIC value of 5.6 mg/ mL against S. epidermidis, S. aureus, E. coli, Bacillus cereus, and V. alginolyticus while penicimarin H (69) and austinol (70) displayed the MIC values of 2.78 mg/mL against S. epidermidis. Penicimarin H (69) displayed the same MIC of 5.56 mg/mL against S. aureus, B. cereus, and V. alginolyticus. Austinol (70) also displayed MIC of 9.17 mg/mL against B. cereus. Ciprofloxacin a positive control inhibited S. epidermidis, S. aureus, E. coli, B. cereus, and V. alginolyticus with MIC values of 0.09, 0.09, 0.19, 0.39 and 0.414 mg/mL, respectively (Huang et al., 2016). An endophytic fungus Penicillium aculeatum (No. 9EB) was isolated from the leaves of K. candel, collected from the Yangjiang, Guangdong province, China served as a source for a new chromone derivative, (20 S*) 2-(20 -hydroxypropyl) 5methyl-7,8-dihydroxy-chromone (71), together with known compounds bacillisporin A (72), and bacillisporin B (73) (Fig. 5). Bacillisporin A (72) and B (73) exhibited potent inhibitory activity against B. subtilis with the same MIC values of 0.067 mg/mL, whereas (20 S*)-2-(20 -hydroxypropyl)5-methyl-7,8-dihydroxy-chromone (71) displayed activity against Salmonella with a MIC value of 0.5 mg/mL (Huang et al., 2017). Three new dihydroisocoumarin derivatives, penicisimpins A, B and C (74, 75 and 76) (Fig. 5), were isolated from Penicillium simplicissimum MA-332, isolated from the rhizosphere of the plant Bruguiera sexangula var. rhynchopetala collected from Hainan Island, P.R. China. These compounds exhibited antimicrobial properties against Aeromonas hydrophilia, E. coli, M. luteus, P. aeruginosa, V. alginolyticus, V. harveyi, and V. parahaemolyticus. (Xu et al., 2016). A new chlorinated metabolite 20 -acetoxy-7-chlorocitreorosein (77) (Fig. 5) obtained from Penicillium citrinum HL-5126 associated with Bruguiera sexangula var. rhynchopetala collected from the South China Sea areas showed activity against V. parahaemolyticus with MIC of 3.76 mg/mL (He et al., 2017).

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Fig. 5. Structures of metabolites isolated from mangrove endophytic fungi with antibacterial activity (54 77).

A new compound penibenzophenone A (78) (Fig. 6) was isolated from the endophytic fungus Penicillium citrinum HL-5126 isolated from the mangrove Bruguiera sexangula var. rhynchopetala collected in the South China Sea. Penibenzophenone A (78) showed antibacterial activity against S. aureus with a MIC value of 20 mg/mL (Zheng et

al., 2018). A new sorbicillin derivative, 2-deoxy-sohirnone C (79) (Fig. 6) obtained from Penicillium sp. GD6 a fungus associated with Chinese mangrove plant Bruguiera gymnorrhiza showed moderate antibacterial activity against Methicillin-resistant Staphylococcus aureus with a MIC value of 80 mg/mL (Jiang et al., 2018).

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Fig. 6. Structures of metabolites isolated from mangrove endophytic fungi with antibacterial activity (78 90) and antimycobacterial activity (91 103).

New sulfide diketopiperazine derivatives, penicibrocazines B (80), C (81), D (82), E (83) and a known congener (84) (Fig. 6) were isolated and identified from Penicillium brocae MA-231, associated with A. marina, collected from Hainan Island, China. They exhibited activity against S. aureus, with MIC values of 32.0, 0.25, 8.0, and 0.25 mg/mL

while positive control chloromycetin gave MIC of 4.0 mg/mL. Penicibrocazine C (81), exhibited MIC value of 0.25 mg/mL against M. luteus. Apart from these, penicibrocazines B, C, D, E and congener (80-84), displayed activity against plant pathogen Gaeumannomyces graminis with MIC values of 0.25, 8.0, 0.25, and 64.0 mg/mL, respectively, while

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the positive control amphotericin B has MIC value of 16.0 mg/mL (Meng et al., 2015). A new polyoxygenated dihydropyrano[2,3-c]pyrrole-4,5‑dione derivative, Pyranonigrin F (85), together with a related known compound, pyranonigrin A (86) (Fig. 6) were isolated from tissue of mangrove plant A. marina inhabiting fungus Penicillium brocae MA-231. Pyranonigrin F (85), and A (86), exhibited potent activity against S. aureus, V. harveyi and V. parahaemolyticus with MIC values of 0.5 mg/ mL, which showed better potency compared to positive control chloromycetin with MICs 156 8.0, 2.0, and 128.0 mg/mL, respectively, for each strain (Meng et al., 2015). One new benzophenone derivative, isomonodictyphenone (87) (Fig. 6), isolated from marine mangrove-derived fungal strain Penicillium sp. MA-37 from the rhizospheric soil of Bruguiera gymnorrhiza collected from Hainan Island, China showed antibacterial activity against Aeromonas hydrophilia with a MIC value of 8 mg/mL, while the positive control, chloromycetin showed MIC value of 4 mg/mL (Luo et al., 2014). A known compound cytosporone E (88) (Fig. 6) isolated from Acremonium strictum associated with mangrove plant Rhizophora apiculate, collected from Cat Ba island, Vietnam, showed MIC value of 4.00 mg/mL against S. aureus (Hammerschmidt et al., 2014). Tricycloalternarene 3a (89), and djalonensone (90) (Fig. 6) were isolated from Alternaria tenuissima EN-192 associated with mangrove plant Rhizophora stylosa, collected from Hainan Island in the South China Sea. These compounds showed its inhibitory potential against V. anguillarum, causing zone of inhibition of 8 and 9 mm diameters, respectively, at 100 mg/disk (Sun et al., 2013).

exhibited potent inhibitory activity against MptpB with an IC50 value of 5.38 mg/mL (Xia et al., 2014). Peniphenone B (99) and peniphenone C (100) (Fig. 6), were isolated from a mangrove fungus, Penicillium dipodomyicola HN4-3A inhabiting the mangrove plant Acanthus ilicifolius collected from the South China Sea, which showed inhibitory activity against MptpB with IC50 values of 0.063 and 0.452 mg/mL, respectively (Li et al., 2014). A novel sesterterpenoid, asperterpenoid A (101) (Fig. 6) possessed a unique carbon skeleton, that was isolated from the endophytic fungus Aspergillus sp. collected from the South China Sea showed strong inhibitory activity against MptpB with an IC50 value of 0.85 mg/mL (Huang et al., 2013). A natural anthraquinone compound, 4-deoxybostrycin (102) and the deoxy-derivative of 4-deoxybostrycin, nigrosporin (103) (Fig. 6) were isolated from Nigrospora sp. isolated from decayed wood of K. candel collected from Mai Po, Hong Kong. They exhibited antimycobecterial activity with thezone of inhibition of 15 and 20 mm, respectively against M. tuberculosis H37Rv reference strain (ATCC 27294) (Wang et al., 2013a). Palmarumycin P1 (104), along with decaspirones A (105) and C (106), palmarumycin CP3, (107) (Fig. 7) belonging to spirodioxynaphthalenes group were extracted from the fungus BCC 25093 isolated from an unidentified mangrove wood collected from Surat Thani province, Thailand. These compounds exhibited antituberculosis activity against M. tuberculosis H37Ra with MIC values of 1.56 mg/mL for Palmarumycin P1 (104) and decaspirone A (105), and 3.13 mg/mL for compounds decaspirone C (106) and palmarumycin CP3 (107) (Bunyapaiboonsri et al., 2015).

3. Anti-mycobacterial compounds

4. Anti-fungal compounds

3.1. Compounds produced by coelomycetes

4.1. Compounds produced by coelomycetes

Diaporisoindole A (91), a novel isoprenylisoindole alkaloid, and together with a precursor tenellone C (92) (Fig. 6) were isolated from the endophytic Diaporthe sp. SYSU-HQ3 obtained from mangrove plant Acanthus ilicifolius collected from Shankou in Guangxi province, China. These compounds exhibited inhibitory activity against M. tuberculosis protein tyrosine phosphatase B (MptpB) with IC50 values of 1.77 and 2.2 mg/mL (Cui et al., 2017a). A new alkenyl phenol and benzaldehyde derivatives pestalol B (93) (Fig. 6), was isolated from endophytic Pestalotiopsis sp. AcBC2 associated with Aegiceras corniculatum collected in Nansha mangrove wetland, Guangdong province, China. In bioluminescence assay, pestalol B (93) showed inhibitory potential against M. tuberculosis when compared to control dimethyl sulfoxide with isoniazid and rifampin as positive drugs (Sun et al., 2014).

A new anthraquinone, 7-(g ,g )-dimethylallyloxymacrosporin (108), along with macrosporin (109), 7-methoxymacrosporin (110), tetrahydroaltersolanol B (111), and altersolanol L (112) (Fig. 7) were isolated from Phoma sp. L28 associated with the mangrove plant collected from Leizhou peninsula, Guangdong Province, China. Macrosporin (109), was found to be the most effective against Colletotrichum musae, C. gloeosporioides, Fusarium graminearum, Penicillium italicum, Fusarium oxysporum, f. sp. lycopersici, and Rhizoctonia solani with MIC values ranging from 3.75 to 100 mg/mL. It exhibited better inhibitory activity against F. oxysporum (MIC 3.75 mg/mL) than that of the positive control, carbendazim (MIC 6.25 mg/mL). The compounds 7-(g ,g )-dimethylallyloxymacrosporin (108), and 7-methoxymacrosporin (110), exhibited average to weak (MICs 80 200 mg/mL) or no (MICs >200 mg/mL) activity against C. musae, C. gloeosporioides, F. graminearum, P. italicum, F. oxysporum, f. sp. lycopersici, and R. solani. Altersolanol L (112), showed antifungal activity against P. italicum and R. solani with MIC values of 35 and 50 mg/mL, respectively, while tetrahydroaltersolanol B (111), was active against only P. italicum with MIC value of 80 mg/mL. Altersolanol L (112), exhibited weak activity towards F. graminearum and C. gloeosporioides with MIC values of 100 and 200 mg/mL, respectively. Carbendazim, a positive control showed antifungal activity against F. oxysporum F. graminearum C. musae, P. italicm R. solani C. gloeosporioides with MIC value of 6.25, 6.25, 6.25, 3.125, 6.25, 12.5 mg/mL (Huang et al., 2017). Known isobenzofuranones, diaporthelactone (113), 7‑hydroxy‑4, 6-dimethyl-3H-isobenzofuran-1-one (114) and 7‑methoxy‑4,6dimethyl-3H-isobenzofuran-1-one (115) (Fig. 7) were extracted from the mangrove endophytic fungus Phomopsis sp. A123 obtained from the foliage of the plant, K. candel collected from the mangrove nature conservation area of Fugong, Fujian, China. Diaporthelactone (113), and 7‑hydroxy‑4,6-dimethyl-3H-isobenzofuran-1-one (114), exhibited antifungal activity against A. niger with MIC values of 50 and 86.4 mg/mL, respectively. The 7‑methoxy‑4,6-dimethyl-3H-isobenzofuran-1-one (115), inhibited the growth of Alternaria alternaria with

3.2. Compounds produced by ascomycetes An alkaloid, talaramide A (94) (Fig. 6), was isolated from endophytic Talaromyces sp. (HZ-YX1) inhabiting healthy leaves of K. obovate collected from the Huizhou Mangrove Nature Reserve in Guangdong Province, China. Talaramide A (94), displayed potent inhibitory activity against mycobacterial PknG with an IC50 value of 18.2 mg/mL (Chen et al., 2017). 3.3. Compounds produced by hyphomycetes Racemic dinaphthalenone derivatives, (§)-asperlone A (95), (§)-asperlone B (96) and a known compound, ( )-mitorubrin (97) (Fig. 4) were isolated from the endophytic Aspergillus sp. 16 5C associated with the leaves of Sonneratia apetala, collected in Hainan Island, China. These compounds showed inhibitory action against MptpB with IC50 values of 1.53, 1.63 and 1.52 mg/mL, respectively (Xiao et al., 2015). A known anthraquinone derivative, (+)-aS-alterporriol C (98) (Fig. 6), isolated from the mangrove fungus, Alternaria sp. (SK11) obtained from the root of Excoecaria agallocha from Shankou, Guangxi Province, China

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Fig. 7. Structures of metabolites isolated from mangrove endophytic fungi with antimycobacterialactivity (104 107) and antifungal activity (108 124).

a MIC value of 96.1 mg/mL (Zhang et al., 2014). The co-culturing of two mangrove fungi, Phomopsis sp. K38 and Alternaria sp. E33, isolated from the South China Sea coast yielded a new polysubstituted benzaldehyde derivative Ethyl 5-ethoxy-2-formyl-3‑hydroxy‑4methyl benzoate (116) (Fig. 7). At 0.063 mg/mL concentration, this

compound inhibited F. graminearum, Gloeosporium musae, R. solani and Phytophthora sojae with zone of inhibition of 12.06, 11.57, 10.21, and 8.50 mm diameter, respectively (Wang et al., 2013b). A new cyclic tetrapeptide, cyclo-(L-leucyl-trans-4‑hydroxy‑L-prolylD-leucyl-trans-4‑hydroxy‑L-proline) (117) (Fig. 7), isolated from the co-

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culture broth of two mangrove fungi, Phomopsis sp. K38 and Alternaria sp. E33 exhibited moderate to high inhibitory activity against four cropthreatening fungi, including G. graminis, Rhizoctonia cerealis, Helminthosporium sativum and F. graminearum with MIC value of 220, 160, 130, and 250 mg/mL, respectively. The positive control triadimefon showed antifungal activity with MIC value of 150, 100, 120, and 150 mg/mL respectively against G. graminis, R. cerealis, H. sativum, and F. graminearum (Li et al., 2014a). Further, the co-culture broth of both the strains was the source of cyclic tetrapeptides, cyclo(d-Pro-L-Tyr-L-Pro-L-Tyr) (118) and cyclo (Gly-L-Phe-L-Pro-L-Tyr) (119) (Fig. 7). Cyclo(d-Pro-L-Tyr-L-Pro-L-Tyr) (Fischer et al., 2016) (118) showed activity against C. albicans, G. graminis, R. cerealis, H. sativum and F. graminearum with MIC value of 35, 300, 250, 350 and 400 mg/mL. The cyclo(Gly-L-Phe-L-Pro-L-Tyr) (119) also exhibited antifungal activity against C. albicans, G. graminis, R. cerealis, H. sativum and F. graminearum with MIC value of 25, 200, 150, 200 and 250 mg/mL, respectively. Positive control, ketoconazole exhibited antifungal activity against C. albicans with MIC value of 2 mg/mL and the another positive control triadimefon exhibited antifungal activity against G. graminis, R. cerealis H. sativum and F. graminearum with MIC value of 150, 100, 120 and 150 mg/mL, respectively (Huang et al., 2014). A new nonadride derivative, (-)-byssochlamic acid imide (120) (Fig. 7), isolated from the co-culture broth of two mangrove fungi (strain Nos. K38 and E33) collected from the South China Sea coast exhibited moderate inhibitory activity toward F. graminearum and F. oxysporum with MIC values of 50 and 60 mg/mL, respectively, while the positive control carbendazim showed (MIC value of 6.25 mg/mL) (Ding et al., 2017). 4.2. Compounds produced by ascomycetes New derivatives of isocoumarin, botryospyrones A (121), B (122), C (123), and a new tryptamine, (3aS, 8aS)-1-acetyl-1, 2, 3, 3a, 8, 8a-hexahydropyrrolo [2,3b] indol-3a-ol (124) (Fig. 7) were isolated from endophytic Botryosphaeria ramosa L29, associated with the leaf of Myoporum bontioides collected from the Leizhou Peninsula, China. Botryospyrone A (121), exhibited activity against F. oxysporum with MIC value of 25.11 mg/mL and weak activity towards F. graminearum with MIC value of 200.75 mg/mL while botryospyrone B (122), showed moderate activity against F. oxysporum, P. italicum, and F. graminearum with MIC value of 25.0, 50.18 and 50.18 mg/mL, respectively. Botryospyrone C (123), exhibited active against F. oxysporum, and F. graminearum with MIC value of 50.1 mg/mL. The compound (3aS, 8aS)-1acetyl-1, 2, 3, 3a, 8, 8a-hexahydropyrrolo [2,3b] indol-3a-ol (124), showed antifungal activity against F. oxysporum, P. italicum, and F. graminearum with MIC value of 6.26, 12.5 and 6.26 mg/mL, respectively. Positive control triadimefon showed antifungal activity with MIC value of 99.9, 2.99, and 149.9 mg/mL respectively against F. oxysporum, P. italicum, and F. graminearum (Wu et al., 2019). The new guignardins B (12), BG1 (14) (Fig. 3) palmarumycin C1 (125) (Fig. 8), spirodioxynaphthalenes were isolated from Guignardia sp. KcF8 inhabiting a mangrove plant K. candel collected from Guangdong province, China. These compounds displayed poor activity against Fusarium sp., at 25 mg/disc; the inhibition zones obtained were 6, 2, and 2 mm, while carbendazim, positive control at same level displayed zone of inhibition of 18 mm. Guignardins B (12), and BG1 (14), showed activity against A. niger, with zones of inhibition 7 and 4 mm, while the positive control carbendazim with 10 mm zone of inhibition. Guignardin BG1 (14), displayed weak activity against F. oxysporum f. sp. cucumeris and R. solani, with an inhibition zone of 2 and 2 mm whereas the positive control carbendazim with zone of inhibition: 12 and 14 mm, respectively (Ai et al., 2014). 4.3. Compounds produced by hyphomycetes Two novels cyclic hexadepsipeptides, fusarihexin A (126) and fusarihexin B (127), and a known compound cyclo-(L-Leu-L-Leu-D-

Leu-L-Leu-L-Val) (128) (Fig. 8) were extracted from the semi-mangrove fungus Fusarium sp. R5 residing inside Myoporum bontioides collected from Leizhou Peninsula, China. Fusarihexin A (126) exhibited potent antifungal activity against three plant pathogens, Colletotrichum gloeosporioides, responsible for causing anthracnose in different vegetables and fruits, C. musae, causing anthracnose and crown rot in bananas, and F. oxysporum Schlecht. f. sp. lycopersici, which causes Fusarium wilt and fruit rot in tomatoes with MIC value of 12.43, 19.96 and 7.73 mg/mL, respectively. Fusarihexin B (127) also showed antifungal activity against C. gloeosporioides, C. musae, and F. oxysporum with MIC value of 12.3, 12.3 and 24.7 mg/mL, respectively. The cyclo(LLeu-L-Leu-D-Leu-L-Leu-L-Val) (128) exhibited moderate activity with MIC values of 50.2, 24.85 and 12.7 mg/mL against C. gloeosporioides C. musae and F. oxysporum, respectively, while the positive control carbendazim showed antifungal activity with the MIC of 12.4, 6.3, and 6.3 mg/mL, respectively (Zhu et al., 2018). The endophytic fungus Aspergillus fumigatus JRJ111048, associated with the leaves of the mangrove plant Acrostichum specioum endemic to Hainan island yielded spiculisporic acid B (129) (Fig. 8). This compound at 20 mg/mL concentration exhibited weak antifungal activity against C. albicans with a zone of inhibition of 8.6 mm, whereas the positive control ketoconazole formed a zone of 29.2 mm (Guo et al., 2017). A new coumarin derivative, 4,40 -dimethoxy-5,50 -dimethyl-7,70 -oxydicoumarin (130), and a new chromone derivative, (S) 5‑hydroxy‑2,6dimethyl-4H-furo[3,4-g]benzopyran-4,8(6H)dione (131), and a new sterone derivative, 24-hydroxylergosta-4,6,8(14),22-tetraen-3-one (132), along with two known bicoumarins, kotanin (133) and orlandin (134) (Fig. 8) were obtained from endophytic Aspergillus clavatus residing inside the root of Myoporum bontioides collected from the Leizhou Peninsula, China. These compounds showed antifungal activity against F. oxysporum, C. musae, and P. italicum (MIC values in the range of 24.37 240.25 mg/ mL). The compound 24-hydroxylergosta-4,6,8(14), 22-tetraen-3-one (132), exhibited good antifungal activity against F. oxysporum, C. musae and P. italicm with MIC values of 10.12, 80.13 and 25.04 mg/mL, respectively. The positive control triadimefon exhibited antifungal activity with the MIC values of 99.9, 80.0, and 49.9 mg/mL, respectively, against tested fungi. Compounds 4,40 -dimethoxy-5,50 -dimethyl-7,70 -oxydicoumarin (130), kotanin (133), and orlandin (134), also exhibited good activity against F. oxysporum with MIC values of 100.28, 103.4, and 103.58 mg/ mL, respectively, which was better than triadimefon whereas compound (S) 5‑hydroxy‑2,6-dimethyl-4H-furo[3,4-g]benzopyran-4,8(6H)dione (131), displayed better inhibitory activity against C. musae, with MIC values of 54.70 mg/mL than triadimefon (Li et al., 2017). Racemic new cyclopentenone and cyclohexenone derivatives, (§)-(4S*,5S*) 2,4,5-trihydroxy-3‑methoxy‑4-methoxycarbonyl5-methyl-2-cyclopenten-1-one (135), and 4‑chloro‑1,5-dihydroxy-3-hydroxymethyl-6-methoxycarbonyl-xanthen-9-one (136) (Fig. 8) were extracted from Alternaria sp. R6 associated with the root of Myoporum bontioides collected in Leizhou peninsula, Guangdong Province, China. The compounds showed antifungal activity against F. graminearum with MIC values of 54.95, and 37.39 mg/mL, respectively (Wang et al., 2015). The new cheatoglobosin, penochalasin I (137), penochalasin J (138), and known chaetoglobosin F (139), C (140) (Fig. 8), A (141), E (142), and armochaetoglobosin I (143) (Fig. 9) were isolated from Penicillium chrysogenum V11 associated with the vein of Myoporum bontioides collected from the Leizhou Peninsula. Chaetoglobosin C (140), A (141), E (142) and armochaetoglobosin I (143) showed activity against R. solani, with MIC values of 12.50, 6.25, 6.25, and 5.96 mg/mL, respectively, the positive control carbendazim exhibited the MIC value of 6.24 mg/mL. The chaetoglobosin C (140), E (142) and penochalasin J (138) showed activity against C. gloeosporioides with MIC values of 25.0, and 12.51, 12.50 mg/mL, respectively, compared to positive control carbendazim (MIC 12.49 mg/ mL). Penochalasin J (138), chaetoglobosin F (139), C (140), A (141), E (142), and armochaetoglobosin I (143) were modestly active

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Fig. 8. Structures of metabolites isolated from mangrove endophytic fungi with Antifungal activity (125 140).

with MIC values ranging from 24.20 53.24 mg/mL against C. musae, C. gloeosporioides, P. italicum, and R. solani. Penochalasin I (137), exhibited weak antifungal activity against R. solani (MIC 100.46 mg/mL) and was inactive against the other three selected fungi (MIC > 200.93 mg/mL) (Huang et al., 2016).

A new chaetoglobosin, penochalasin K (144) (Fig. 9), was isolated from the mangrove endophytic fungus Penicillium chrysogenum V11 obtained from Myoporum bontioides collected from Guangdong Province, China. Penochalasin K (144) displayed a significant inhibitory activity against C. gloeosporioides and R. solani (MIC of 3.13 and 6.26 mg/mL,

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Fig. 9. Structures of metabolites isolated from mangrove endophytic fungi with Antifungalactivity (141 150) and antiviral activity (151 159).

respectively), while positive control carbendazim exhibited antifungal activity with MIC of 12.49 and 6.24 mg/mL, respectively (Zhu et al., 2017). (Z) 7,40 -dimethoxy-6‑hydroxy‑aurone-4-O-b‑gluco‑pyranoside (145) (Fig. 9) isolated from endophytic Penicillium sp. FJ-1 exhibited antifungal activity against Candida spp. (Candida krusei ATCC62578, Candida krusei CK5, C. albicans ATCC18804, C. albicans CA12, Candida glabrata ATCC90030, Candida glabrata CG5, Candida parapsilosis ATCC 22,014, C. tropicalis ATCC 13,803 C. tropicalis CT2) with the MIC in the range of 1.5 2.5. mg/mL with the potency comparable to amphotericin B and much better than fluconazole (Song et al., 2015). Two sesquiterpenes, penicibilaenes A (146) and B (147) (Fig. 9), were isolated from endophytic Penicillium bilaiae MA-267 from rhizospheric soil of the mangrove

plant Lumnitzera racemosa. Penicibilaenes A (146) and B (147) exhibited selective activity against the plant pathogenic fungus C. gloeosporioides (MIC of 1.0 and 0.125 mg/mL, respectively) (Meng et al., 2014). A polyoxygenated dihydropyrano[2,3-c] pyrrole-4,5‑dione derivative, pyranonigrin F (148), along with pyranonigrin A (149) (Fig. 9) were extracted from endophytic fungus Penicillium brocae MA-231, obtained from a mangrove plant A. marina. Pyranonigrin F (148) and A (149) exhibited good activity against plant pathogens, Alternaria brassicae and C. gloeosprioides with MICs of 0.5 mg/ mL, which showed better efficacy than bleomycin, positive control (with MICs 32.0 and 4.0 mg/mL, respectively, for each strain) (Meng et al., 2015).

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4.4. Compounds produced by basidiomycetes Tremulenolide A (150) (Fig. 9), extracted from Flavodon flavus PSUMA201 associated with Rhizophora apiculata from Songkhla province, Thailand, displayed antifungal activity against Cryptococcus neoformans ATCC90113 with MIC value of 128 mg/mL (Klaiklay et al., 2013). 5. Antiviral compounds 5.1. Compoundsproduced by coelomycetes Five alkenyl phenol and benzaldehyde derivatives, pestalols A (151), B (93) C, D, E (152, 153, 154), and transharzialactones A (155), F (156), 3b, 5a, 9a-trihydroxy-7, 22-en-ergost-6-one (157) and 3b‑hydroxy‑sterol (158) (Fig. 9), were isolated from endophytic fungus Pestalotiopsis sp. AcBC2 from the inner stems of a Chinese mangrove plant Aegiceras corniculatum collected in Nansha mangrove wetland, Guangdong province, China. These compounds displayed potency to different extents against the replication of A/HK/8/68 (H3N2) virus and A/ WSN/33 (H1N1). The compound 3b‑ hydroxy‑sterol (158) exhibited inhibitory activity with IC50 of 1.93 mg/ mL for virus A/HK/8/68 (H3N2) and IC50 of 0.90 mg/ mL for A/WSN/33 (H1N1) (Sun et al., 2014). Vaccinal A (159) (Fig. 9), a new naphthalene derivative, was isolated from Pestalotiopsis vaccinii (cgmcc3.9199) from a branch of K. candel, distributed in coastal and estuarine areas of southern China. Vaccinal A (159) exhibited in vitro anti-enterovirus 71 (EV71) with an IC50 value of 3.88 mg/mL (Wang et al., 2014). A new salicyloid derivative, vaccinol J (160) (Fig. 10), was also isolated from Pestalotiopsis vaccinii (cgmcc3.9199). Vaccinol J (160) exhibited in vitro anti-enterovirus 7l (EV71) with an IC50 value of 8.36 mg/mL, and the inhibition effect was stronger than positive control ribavirin (IC50 43.22 mg/mL) (Wang et al., 2017). 5.2. Compounds produced by ascomycetes Neosartoryadins A (161) and B (162) (Fig. 10), Fumiquinazoline alkaloids were isolated from the endophytic fungus Neosartorya udagawae HDN13-313. Neosartoryadins A (161) and B (162) displayed anti-influenza virus A (H1N1) activities with IC50 values of 32.11 and 29.14 mg/mL, respectively while the ribavirin, a positive control showed an, IC50 of 22.95 mg/mL (Yu et al., 2015).

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Moreover, against H1N1 viral neuraminidase (NA), only isoaspulvinone E (170) displayed inhibitory potential (IC50 62.14 mg/mL), and docking of two isomers isoaspulvinone E (170) and aspulvinone E (171) into the active sites of NA showed that the E double bond D 5 (10) was compulsory to achieve activity (Gao et al., 2013). Simpterpenoid A (173) (Fig. 10), an unprecedented meroterpenoid was isolated from Penicillium simplicissimum MA-332 inhabiting rhizospheric soil of mangrove plant Bruguiera sexangula var. rhynchopetala, collected from Hainan island, in the South China sea. This compound exhibited potent antiviral activity against influenza neuraminidase with an IC50 value of 0.003 mg/mL while positive control oseltamivir exhibit antiviral activity with an IC50 value of 0.00099 mg/mL (Li et al., 2018). The new brefeldins E1 E5 (174 178) along with known brefeldin A (179), brefeldin A 7-O-acetate (180), alternariol-5-O-methyl ether (181), 30 -hydroxyalternariol-5-O-methyl ether (182), mangrovamides A (183) (Fig. 10), were isolated from endophytic fungus, Penicillium sp. associated with the healthy root of Panax notoginseng collected from Wenshan, Yunnan province of China. Brefeldin E1 E5 (174 178) and alternariol-5-O-methyl ether (181), 30 -hydroxyalternariol-5-O-methyl ether (182) and mangrovamides A (183) exhibited weak antiviral activity while the compounds brefeldin A (179) and brefeldin A 7-O-acetate (180), exhibited potent antiviral (HCV, HBV) with ID50 value ranging from 4.03 mg/mL to 7.09 mg/mL, respectively (Xie et al., 2017).

6. Strategies to enhance the production of secondary metabolites Microbes produce bioactive compounds in low quantities as part of defence mechanisms against various stresses. We often implement methods like process optimization, strain improvement, one strainmany compounds (OSMAC), epigenetic modulation, subjecting microbes to stress to enhance the yield of secondary metabolites. Out of these, epigenetic modulators have proven efficient in producing newer metabolites that are generally not produced by other approaches in laboratory settings. Fungal genome projects have revealed that genes about the biosynthesis of secondary metabolites are often silent and do not express. Deciphering these biosynthetic pathways needs modern solutions like the use of genetic tools, better knowledge of secondary metabolite regulatory pathways. The strategies mentioned below aid in the discovery of cryptic natural products. Using different methodologies to activate these genes would certainly produce newer metabolites for the pharma industry.

5.3. Compounds produced by hyphomycetes 6.1. Co-cultivation or mixed fermentation Endophytic fungus, Trichoderma sp. Xy24 was isolated from the leaves, stems and peels of mangrove plant Xylocarpus granatum collected in Sanya district, Hainan province of China was the source of trichodimerol (163) (Fig. 10). It exhibited moderate inhibitory activity with an IC50 value of 37.03 mg/mL, using an NA (H7N9)/MUNANA model (Zhang et al., 2014). The new indole alkaloids including a new glyantrypine derivatives oxoglyantrypine (164) (Fig. 8), a new pyrazinoquinazoline derivative norquinadoline A (165), together with known alkaloids deoxynortryptoquivaline (166), and deoxytryptoquivaline (167), tryptoquivaline (168) and quinadoline B (169) (Fig. 10), were isolated from the mangrove-derived fungus Cladosporium sp. PJX-41 from soil around a mangrove collected in Guangzhou, China. These compounds exhibited significant activities against influenza virus A (H1N1), with IC50 values of in the range of 29.27 39.11 mg/mL (Peng et al., 2013). A new butenolide isoaspulvinone E (170), aspulvinone E (171) and pulvic acid (172) (Fig. 10), were obtained from the marine-derived fungus, Aspergillus terreus Gwq-48 isolated from a mangrove rhizosphere soil sample collected in the coast of Fujian province, China. These compounds showed significant anti-influenza A H1N1 virus activities, with IC50 values of 32.3, 56.9, and 29.1 mg/mL, respectively.

It refers to culturing of two or more microorganisms together in laboratory settings to create competition amongst species and provoke to activate silent biosynthetic genes from these organisms, which remain silent in typical situations. In co-cultivation, microorganisms are either antagonized or faces limited resources, which activate defence strategies for survival leading to the production of bioactive metabolites. In vitro culture of microorganisms limits chemical diversity of metabolites. Co-cultivation significantly has paved the way to enhance the production of cryptic compounds that doesn’t appear in axenic cultures of producing strain (Marmann et al., 2014). Mixed fermentation offers another alternative method to achieve new compounds to hasten drug discovery. Pestalone was one such antimicrobial compound obtained through mixed fermentation of fungus with bacteria (Cueto et al., 2001). Emericellamides A and B displayed antibacterial activity that was derived from co-cultivation of marine-derived fungus Emericella sp., actinomycete Salinispora arenicola (Oh et al., 2007). Likewise, compounds aspergicin, neoaspergillic acid, ergosterol were isolated using co-culture of mangrove epiphyte, exhibited activity against selected Gram-positive bacteria (Zhu et al., 2011).

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Fig. 10. Structures of metabolites isolated from mangrove endophytic fungi with antiviral activity (160 183).

6.2. Activation of silent biosynthetic genes using epigenetic modulation Past studies on fungal genome have confirmed the existence of silent gene clusters responsible for the production of secondary metabolites (Brakhage and Schroeckh, 2011). Epigenetics exploits regulating expression of genes controlled by environmental factors

and are independent of DNA sequences. Epigenetics dynamically regulates these silent gene clusters (Cichewicz, 2010). Gene clusters involved in the synthesis of secondary metabolites often remain inactive or silent in laboratory conditions (Rutledge and Challis, 2015). Epigenetic modulators can induce these silent genes in endophytes which have resulted in the production of many more and new

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compounds (Fischer et al., 2016). Epigenetic modulators regulate gene transcription of endophytic fungi which can be employed to elicit the expression level of genes without prior information about species genome. The fungal genome contains biosynthetic gene clusters (BGCs) that encode for secondary metabolites, and these BGCs lie in heterochromatin region which rarely expresses in normal laboratory settings. Chemical inhibitors aid in inducing the expression of cryptic genes of the fungal genome (Pfannenstiel and Keller, 2019) to enhance the production of secondary metabolites. Endophytes are challenged with various chemical elicitors, precursor molecules, or epigenetic modulation into action. DNA methylation and histone deacetylase activity regulate gene clusters responsible for secondary metabolite biosynthesis (Cherblanc et al., 2012). Inhibitors like suberoylanilide hydroxamic acid (SAHA), sodium butyrate which modulates histone deacetylase (HDAC) activity or inhibitors of DNA methylation like procaine, 5-aza-20-deoxycytidine,5-azacytidine (AZA), are commonly practiced for activation of biosynthetic pathways involved in biosynthesis of secondary fungal metabolites that stays silent in normal laboratory conditions (Shwab et al., 2007; Cichewicz 2010; Demers et al., 2018). SAHA, which causes inhibition of HDAC activity and AZA induces hypomethylation, are widely used to target biosynthetic pathways. These alternative methods will undoubtedly provide a boost to the discovery of bioactive metabolites exploiting interspecies cross-talk among microorganisms. 7. Challenges in endophyte research Although the application of epigenetic modification needs detail omics knowledge, availability of genome data poses hurdle in its applicability. Apart from these, our confined knowledge regarding evolution, ecology, interaction pattern with plants and other microbes makes discovery process cumbersome. Another hurdle in progress offers identification of the potential isolates producing bioactive compounds is a tedious process that needs tremendous screening to obtain a novel compound. In addition, major bottleneck obstacle in deciphering bioactive compounds from endophytes is attenuation of compounds in lab condition with decrease in yield along with repeated sub-culturing. In natural condition, multiple factors, interaction process determine the production of bioactive compounds whose imitation in lab condition is bit difficult. Up to certain extent use of co-cultivation and addition of certain plant based compounds may serve the purpose. However, genome mining approaches can be employed to hasten the discovery process. With the recent advances in CRISPR/Cas9 based genome editing tools modification of biosynthetic pathways for secondary metabolite production have become much more feasible. As previously mentioned cryptic gene clusters responsible for biosynthesis of secondary metabolites might facilitate endophytic research. Identification of marker genes for secondary metabolites production may help in intensifying the screening and production. Intensive studies on endophyte and host plant interaction, omics based approaches promise to overcome the present hurdles and give boost to endophyte based metabolites production. 8. Conclusions Mangrove endophytic fungi are a promising source of bioactive metabolites possessing unique structural features with a broad range of biological activities. The extreme conditions persisting in the mangrove region confer natural to stress over mangrove plants and associated microorganisms that are believed to produce diverse secondary metabolites required crucially for their existence. Natural products obtained from endophytic fungi can be a promising source of bioactive metabolites against drug-resistance pathogens. In the present review, we have described 183 compounds isolated from mangrove fungi out of which 91, 42, 33 and 17 have been reported to possess antibacterial, antifungal, antiviral and antimycobacterial activity, respectively. These metabolites also display chemical

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diversity, belongs to various chemical classes (Table 2) which include peptide molecules viz. cyclo(d-Pro-L-Tyr-L-Pro-L-Tyr) (118) and cyclo(Gly-L-Phe-L-Pro-L-Tyr) (119), fusarihexin A (126) and fusarihexin B (127), and cyclo(L-Leu-L-Leu-D-Leu-L-Leu-L-Val) (128) and glycoside (145) as well as cytochalasin alkaloids (Penochalasin I (137), penochalasin J (138), chaetoglobosin F (139), C, (140) A, (141), E, (142) and armochaetoglobosin I (143), penochalasin K (144), depside (Diaporthelactone (113), 7‑hydroxy‑4,6-dimethyl-3H- isobenzofuran-1-one (114) and 7‑methoxy‑4,6-dimethyl-3H-isobenzofuran1-one (115). Diverse scaffolds with a different mode of action discovered during studies may play an important role in drug discovery. It is also observed that in most of the cases only in vitro activity is demonstrated and requires in vivo and mode of action studies. Furthermore, the literature surveys have shown that to date a confined chemical investigation has been conducted on metabolites of mangrove endophytic fungi, so their enormous potential for producing novel bioactive metabolites must be directed way forward to procure novel metabolites that will hasten the process of drug discovery. Epigenetic approaches can further help to translate the production of bioactive metabolites at greater scale and can fill a gap in research domain of fungal endophyte. Compared to plants derived metabolites, endophytic fungi offers better yield and easy manipulation using epigenetic modifiers makes it perfect candidate for future pharmaceutical application. Till date, plethora of novel compounds with bioactivity has been discovered and have opened new avenues of research but reasonable commercial implementation seeks attention. Accordingly, a rich pool of mangrove endophytic fungi is still unexplored, and that needs further investigations for the discovery of novel bioactive molecules in the coming years. Declaration of Competing Interest There is no conflict of interest. Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1016/j.sajb.2020.01.006. References Agrawal, S., Barrow, C.J., Deshmukh, S.K., 2019. Marine fungi: A potential source of future cosmeceuticals. In: Satyanarayana, T., Deshmukh, S.K., Deshpande, M.V. (Eds.), Advancing Frontiers in Mycology and Mycotechnology: Basic and Applied Aspects of Fungi. Nature Singapore Pte Ltd., pp. 1–40. https://doi.org/10.1007/978-981-13-9349-5_25. Ai, W., Wei, X., Lin, X., Sheng, L., Wang, Z., Tu, Z., et al., 2014. Guignardins A F, spirodioxynaphthalenes from the endophytic fungus Guignardia sp. kcf8 as a new class of ptp1b and SIRT1 inhibitors. Tetrahedron 70, 5806–5814. Alongi, D.M., 2002. Present state and future of the world's mangrove forests. Environmental Conservation 29, 331–349. Alurappa, R., Chowdappa, S., Narayanaswamy, R., Sinniah, U.R., Mohanty, S.K., Swamy, M.K., 2018. Endophytic fungi and bioactive metabolites production: An update, microbial biotechnology. Springer, pp. 455–482. Bai, Z.Q., Lin, X., Wang, Y., Wang, J., Zhou, X., Yang, B., et al., 2014. New phenyl derivatives from endophytic fungus Aspergillus flavipes AIL8 derived of mangrove plant Acanthus ilicifolius. Fitoterapia 95, 194–202. Brakhage, A.A., Schroeckh, V., 2011. Fungal secondary metabolites strategies to activate silent gene clusters. Fungal Genetics and Biology 48 (1), 15–22. Bunyapaiboonsri, T., Yoiprommarat, S., Nopgason, R., Intereya, K., Suvannakad, R., Sakayaroj, J., 2015. Palmarumycins from the mangrove fungus bcc 25093. Tetrahedron 71, 5572–5578. Cai, R., Chen, S., Liu, Z., Tan, C., Huang, X., She, Z., 2017a. A new a-pyrone from the mangrove endophytic fungus Phomopsis sp. hny29-2b. Natural Product Research 31, 124–130. Cai, R., Chen, S., Long, Y., Li, C., Huang, X., She, Z., 2017b. Depsidones from Talaromyces stipitatus SK-4, an endophytic fungus of the mangrove plant Acanthus ilicifolius. Phytochemistry Letters 20, 196–199. Chen, S., Chen, D., Cai, R., Cui, H., Long, Y., Lu, Y., et al., 2016a. Cytotoxic and antibacterial preussomerins from the mangrove endophytic fungus Lasiodiplodia theobromae ZJ-HQ1. Journal of Natural Products 79, 2397–2402. Chen, S., He, L., Chen, D., Cai, R., Long, Y., Lu, Y., et al., 2017b. Talaramide A, an unusual alkaloid from the mangrove endophytic fungus Talaromyces sp.(HZ-YX1) as an inhibitor of mycobacterial pkng. New Journal of Chemistry 41, 4273–4276.

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Chen, S., Liu, Y., Liu, Z., Cai, R., Lu, Y., Huang, X., et al., 2016b. Isocoumarins and benzofurans from the mangrove endophytic fungus Talaromyces amestolkiae possess a-glucosidase inhibitory and antibacterial activities. RSC Advances 6, 26412– 26420. Chen, Y., Liu, Z., Liu, H., Pan, Y., Li, J., Liu, L., et al., 2018. Dichloroisocoumarins with potential anti-inflammatory activity from the mangrove endophytic fungus Ascomycota sp. CYSK-4. Marine Drugs 16, 54. Chen, M., Shen, N.X., Chen, Z.Q., Zhang, F.M., Chen, Y., 2017a. Penicilones A D, antimrsa azaphilones from the marine-derived fungus Penicillium janthinellum HK1-6. Journal of Natural Products 80, 1081–1086. Cherblanc, F., Chapman-Rothe, N., Brown, R., Fuchter, M.J., 2012. Current limitations and future opportunities for epigenetic therapies. Future Medicinal Chemistry 4 (4), 425–446. Cichewicz, R.H., 2010. Epigenome manipulation as a pathway to new natural product scaffolds and their congeners. Natural product reports 27 (1), 11–22. Cueto, M., Jensen, P.R., Kauffman, C., Fenical, W., Lobkovsky, E., Clardy, J., 2001. Pestalone, a new antibiotic produced by a marine fungus in response to bacterial challenge. Journal of Natural Products 64 (11), 1444–1446. Cui, H., Lin, Y., Luo, M., Lu, Y., Huang, X., She, Z., 2017a. Diaporisoindoles A C: Three isoprenylisoindole alkaloid derivatives from the mangrove endophytic fungus Diaporthe sp. SYSU-HQ3. Organic Letters 19, 5621–5624. Cui, H., Liu, Y., Ding, M., Zhang, Z., Liu, H., Huang, X., She, Z., 2017b. New pyranonaphthazarin and 2-naphthoic acid derivatives from the mangrove endophytic fungus Leptosphaerulina sp. SKS032. Phytochemistry Letters 20, 214–217. Dahibhate, N.L., Saddhe, A.A., Kumar, K., 2019. Mangrove plants as a source of bioactive compounds: A review. The Natural Products Journal 9, 86–97. Das, G., Gouda, S., Mohanta, Y.K., Patra, J.K., 2015. Mangrove plants: A potential source for anticancer drugs. IJMS 44 (05), 666–672. Debbab, A., Aly, A.H., Proksch, P., 2013. Mangrove derived fungal endophytes a chemical and biological perception. Fungal Diversity 61, 1–27. Demers, D., Knestrick, M., Fleeman, R., Tawfik, R., Azhari, A., Souza, A., et al., 2018. Exploitation of mangrove endophytic fungi for infectious disease drug discovery. Marine Drugs 16 (10), 376. Deshmukh, S.K., 2018. Translating endophytic fungal research towards pharmaceutical applications. Kavaka 50, 1–13. Deshmukh, S.K., Gupta, M.K., Prakash, V., Reddy, M.S., 2018b. Mangrove-associated fungi a novel source of potential anticancer compounds. Journal of Fungi 4, 101. https://doi.org/10.3390/jof4030101. Deshmukh, S.K., Prakash, V., Ranjan, N., 2018a. Marine fungi: a potential source of cytotoxic compounds. Frontiers in Microbiology. https://doi.org/10.3389/ fmicb.2017.02536. Deshmukh, S.K., Verekar, S.A., Bhave, S.V., 2015. Endophytic fungi: A reservoir of antibacterials. Frontiers in Microbiology 2015 (5), 715. Ding, W., Lu, Y., Feng, Z., Luo, S., Li, C., 2017. A new nonadride derivative from the co-culture broth of two mangrove fungi. Chemistry of Natural Compounds 53, 691–693. Fischer, J., Schroeckh, V., Brakhage, A.A., 2016. Awakening of fungal secondary metabolite gene clusters. In Gene Expression Systems in Fungi: Advancements and Appli€ ck, C., editors. (Cham: Springer International cations, eds Schmoll M., Dattenbo Publishing), 253–273. https://doi.org/10.1007/978-3-319-27951-0_11. Gao, H., Guo, W., Wang, Q., Zhang, L., Zhu, M., Zhu, T., et al., 2013. Aspulvinones from a mangrove rhizosphere soil-derived fungus Aspergillus terreus gwq-48 with antiinfluenza a viral (H1N1) activity. Bioorganic Medicinal Chemistry Letters 23, 1776– 1778. Giri, C., Ochieng, E., Tieszen, L.L., Zhu, Z., Singh, A., Loveland, T., et al., 2011. Status and distribution of mangrove forests of the world using earth observation satellite data. Global Ecology and Biogeography 20, 154–159. Gunatilaka, A.A.L., 2006. Natural products from plant-associated microorganisms: Distribution, structural diversity,bioactivity, and implications of their occurrence. Journal of Natural Products 69, 509–526. Guo, Z.K., Zhou, Y.Q., Han, H., Wang, W., Xiang, L., Deng, X.Z., et al., 2018. New antibacterial phenone derivatives asperphenone A C from mangrove-derived fungus Aspergillus sp. YHZ-1. Marine Drugs 16, 45. Guo, Z., Gai, C., Cai, C., Chen, L., Liu, S., Zeng, Y., et al., 2017. Metabolites with insecticidal activity from Aspergillus fumigatus JRJ111048 isolated from mangrove plant Acrostichum specioum endemic to hainan island. Marine Drugs 15, 381. Hammerschmidt, L., Debbab, A., Ngoc, T.D., Wray, V., Hemphil, C.P., Lin, W., et al., 2014. Polyketides from the mangrove-derived endophytic fungus Acremonium strictum. Tetrahedron Letters 55, 3463–3468. He, K.Y., Zhang, C., Duan, Y.R., Huang, G.L., Yang, C.Y., Lu, X.R., et al., 2017. New chlorinated xanthone and anthraquinone produced by a mangrove-derived fungus Penicillium citrinum HL-5126. The Journal of Antibiotics 70, 823. Heinig, U., Scholz, S., Jennewein, S., 2013. Getting to the bottom of taxol biosynthesis by fungi fungal diversity, 60, 161 170. Hemberger, Y., Xu, J., Wray, V., Proksch, P., Wu, J., Bringmann, G., 2013. Pestalotiopens a and B: Stereochemically challenging flexible sesquiterpene cyclopaldic acid hybrids from Pestalotiopsis sp. Chemistr A European Journal 19, 15556–15564. Huang, S., Chen, H., Li, W., Zhu, X., Ding, W., Li, C., 2016b. Bioactive chaetoglobosins from the mangrove endophytic fungus Penicillium chrysogenum. Marine Drugs 14, 172. Huang, S., Ding, W., Li, C., Cox, D.G., 2014. Two new cyclopeptides from the co-culture broth of two marine mangrove fungi and their antifungal activity. Pharmacognosy Magazine 10, 410. Huang, H., Liu, T., Wu, X., Guo, J., Lan, X., Zhu, Q., et al., 2017a. A new antibacterial chromone derivative from mangrove-derived fungus Penicillium aculeatum (No. 9EB). Natural Product Research 31, 2593–2598.

Huang, X., Huang, H., Li, H., Sun, X., Huang, H., Lu, Y., et al., 2013. Asperterpenoid A, a new sesterterpenoid as an inhibitor of Mycobacterium tuberculosis protein tyrosine phosphatase b from the culture of Aspergillus sp. 16-5c. Organic Letters 15, 721– 723. Huang, S., Xu, J., Li, F., Zhou, D., Xu, L., Li, C., 2017b. Identification and antifungal activity of metabolites from the mangrove fungus Phoma sp. L28. Chemistry of Natural Compounds 53, 237–240. Huang, G.L., Zhou, X.M., Bai, M., Liu, Y.X., Zhao, Y.L., Luo, Y.P., et al., 2016a. Dihydroisocoumarins from the mangrove-derived fungus Penicillium citrinum. Marine Drugs 14, 177. Hyde, K., Soytong, K., 2008. The fungal endophyte dilemma. Fungal Diversity 33, e173. Imhoff, J., 2016. Natural products from marine fungi—Still an underrepresented resource. Marine Drugs 14 (1), 19. https://doi.org/10.3390/md14010019. Jiang, C.S., Zhen, F.Z., Xiao, H.Y., Le, F.L., Yu, C.G., Bo, P.Y., et al., 2018. Antibacterial sorbicillin and diketopiperazines from the endogenous fungus Penicillium sp. GD6 associated chinese mangrove Bruguiera gymnorrhiza. Chinese Journal of Natural Medicines 16, 358–365. Kharwar, R.N., Mishra, A., Gond, S.K., Stierle, A., Stierle, D., 2011. Anticancer compounds derived from fungal endophytes: Their importance and future challenges. Natural Product Reports 28, 1208–1228. Klaiklay, S., Rukachaisirikul, V., Phongpaichit, S., Buatong, J., Preedanon, S., Sakayaroj, J., 2013. Flavodonfuran: a new difuranylmethane derivative from the mangrove endophytic fungus Favodon flavus PSU-MA201. Natural Product Research 27, 1722–1726. Kohlmeyer, J., Kohlmeyer, E., 1979. Marine Mycology. The Higher Fungi. Marine Mycology. The Higher Fungi. Academic Press, New York, p. 690. Koulman, A., Lee, T.V., Fraser, K., Johnson, L., Arcus, V., Lott, J.S., et al., 2012. Identification of extracellular siderophores and a related peptide from the endophytic fungus Epichlo€e festucae in culture and endophyte-infected Lolium perenne. Phytochemistry 75, 128–139. Li, H.Y., Wei, D.Q., Shen, M., Zhou, Z.P., 2012. Endophytes and their role in phytoremediation. Fungal Diversity 54, 11–18. Li, X.B., Chen, G.Y., Liu, R.J., Zheng, C.J., Song, X.M., Han, C.R., 2017b. A new biphenyl derivative from the mangrove endophytic fungus Phomopsis longicolla HL-2232. Natural Product Research 31, 2264–2267. Li, H., Jiang, J., Liu, Z., Lin, S., Xia, G., Xia, X., et al., 2014b. Peniphenones a d from the mangrove fungus Penicillium dipodomyicola HN4-3A as inhibitors of Mycobacterium tuberculosis phosphatase mptpb. Journal of Natural Products 77, 800–806. Li, C., Wang, J., Luo, C., Ding, W., Cox, D.G., 2014a. A new cyclopeptide with antifungal activity from the co-culture broth of two marine mangrove fungi. Natural Product Research 28, 616–621. Li, W., Xiong, P., Zheng, W., Zhu, X., She, Z., Ding, W., et al., 2017a. Identification and antifungal activity of compounds from the mangrove endophytic fungus Aspergillus clavatus R7. Marine drugs 15, 259. Li, H.L., Xu, R., Li, X.M., Yang, S.Q., Meng, L.H., Wang, B.G., 2018. Simpterpenoid A, a meroterpenoid with a highly functionalized cyclohexadiene moiety featuring gem-propane-1,2-dione and methylformate groups, from the mangrove-derived Penicillium simplicissimum MA-332. Organic Letters 20, 1465–1468. Liu, D., Li, X.M., Li, C.S., Wang, B.G., 2013. Nigerasterols a and B, antiproliferative sterols from the mangrove derived endophytic fungus Aspergillus niger MA 132. Helvetica Chimica Acta 96, 1055–1061. Liu, Y., Li, X.M., Meng, L.H., Wang, B.G., 2015. Polyketides from the marine mangrovederived fungus Aspergillus ochraceus MA-15 and their activity against aquatic pathogenic bacteria. Phytochemistry Letters 12, 232–236. Luo, H., Li, X.M., Li, C.S., Wang, B.G., 2014. Diphenyl ether and benzophenone derivatives from the marine mangrove-derived fungus Penicillium sp. MA-37. Phytochemistry Letters 9, 22–25. Marmann, A., Aly, A., Lin, W., Wang, B., Proksch, P., 2014. Co-cultivation—a powerful emerging tool for enhancing the chemical diversity of microorganisms. Marine Drugs 12 (2), 1043–1065. Meng, L.H., Du, F.Y., Li, X.M., Pedpradab, P., Xu, G.M., Wang, B.G., 2015a. Rubrumazines A C, indolediketopiperazines of the isoechinulin class from Eurotium rubrum MA150, a fungus obtained from marine mangrove-derived rhizospheric soil. Journal of Natural Products 78, 909–913. Meng, L.H., Li, X.M., Liu, Y., Wang, B.G., 2014. Penicibilaenes a and B, sesquiterpenes with a tricyclo [6.3. 1.01, 5] dodecane skeleton from the marine isolate of Penicillium bilaiae MA-267. Organic Letters 16, 6052–6055. Meng, L.H., Li, X.M., Liu, Y., Wang, B.G., 2015b. Polyoxygenated dihydropyrano [2, 3-c] pyrrole-4, 5-dione derivatives from the marine mangrove-derived endophytic fungus Penicillium brocae MA-231 and their antimicrobial activity. Chinese Chemical Letters 26, 610–612. Meng, L.H., Li, X.M., Liu, Y., Xu, G.M., Wang, B.G., 2017. Antimicrobial alkaloids produced by the mangrove endophyte Penicillium brocae MA-231 using the osmac approach. RSC Advances 7, 55026–55033. ndi, A., Li, X.M., Liu, Y., Kurtan, T., Wang, B.G., 2016b. Isolation, steMeng, L.H., Ma reochemical study, and antioxidant activity of benzofuranone derivatives from a mangrove derived fungus Eurotium rubrum MA 150. Chirality 28, 581–584. Meng, L.H., Wang, C.Y., Mandi, A., Li, X.M., Hu, X.Y., Kassack, M.U., et al., 2016a. Three diketopiperazine alkaloids with spirocyclic skeletons and one bisthiodiketopiperazine derivative from the mangrove-derived endophytic fungus Penicillium brocae MA-231. Organic Letters 18, 5304–5307. Meng, L.-H., Zhang, P., Li, X.-M., Wang, B.-G., 2015c. Penicibrocazines A E, five new sulfide diketopiperazines from the marine-derived endophytic fungus Penicillium brocae. Marine Drugs 13, 276–287.

Please cite this article as: S.K. Deshmukh et al., Anti-infectives from mangrove endophytic fungi, South African Journal of Botany (2020), https://doi.org/10.1016/j.sajb.2020.01.006

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ARTICLE IN PRESS S.K. Deshmukh et al. / South African Journal of Botany 00 (2020) 1 27

€llner, L., Franken, P., Andrade-Linares, D., 2016. Phosphate utilizaNgwene, B., Boukail, S., So tion by the fungal root endophyte Piriformospora indica. Plant and Soil 405, 231–241. Nurunnabi, T.R., Nahar, L., Al Majmaie, S., Rahman, S.M., Sohrab, M.H., Billah, M.M., et al., 2018. Anti MRSA activity of oxysporone and xylitol from the endophytic fungus Pestalotia sp. growing on the sundarbans mangrove plant Heritiera fomes. Phytotherapy Research 32, 348–354. Oh, D.C., Kauffman, C.A., Jensen, P.R., Fenical, W., 2007. Induced production of emericellamides A and B from the marine-derived fungus Emericella sp. in competing coculture. Journal of Natural Products 70 (4), 515–520. Peng, J., Lin, T., Wang, W., Xin, Z., Zhu, T., Gu, Q., et al., 2013. Antiviral alkaloids produced by the mangrove-derived fungus Cladosporium sp. PJX-41. Journal of Natural Products 76, 1133–1140. Pfannenstiel, B.T., Keller, N.P., 2019. On top of biosynthetic gene clusters: how epigenetic machinery influences secondary metabolism in fungi. Biotechnology advances.. Rutledge, P.J., Challis, G.L., 2015. Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nature Reviews Microbiology 13, 509–523. https://doi.org/10.1038/nrmicro3496. Salini, G., 2015. Pharmacological profile of mangrove endophytes - A Review. Int J Pharm Pharm Sci 7, 6–15. Shearer, C., Descals, E., Kohlmeyer, B., Kohlmeyer, J., Marvanova, L., Padgett, D., et al., 2007. Fungal biodiversity in aquatic habitats. Biodiversity and Conservation 16, 49–67. Shwab, E.K., Bok, J.W., Tribus, M., Galehr, J., Graessle, S., Keller, N.P., 2007. Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryotic Cell 6 (9), 1656–1664. Song, Y., Ma, Q., Li, J., 2015. A new aurone glycoside with antifungal activity from marine-derived fungus Penicillium sp. FJ-1. China Journal of Chinese Materia Medica 40, 1097–1101. Souza Sebastianes, F.L., Montes Peral Valente, A.M., Boffo, E.F., Ferreira, A.G., Melo, I.S., Beraldo Moraes, L.A., et al., 2017. Isolation of the antibacterial agent viridiol from the mangrove endophytic fungus Hypocrea virens, as monitored by a biologic assay against Escherichia coli and NMR spectroscopy. Current Biotechnology 6, 325–332. Strobel, G., Daisy, B., Castillo, U., Harper, J., 2004. Natural products from endophytic microorganisms. Journal of Natural Products 67, 257–268. Sun, H., Gao, S., Li, X., Li, C., Wang, B., 2013. Chemical constituents of marine mangrovederived endophytic fungus Alternaria tenuissima EN-192. Chinese Journal of Oceanology and Limnology 31, 464–470. Sun, J.F., Lin, X., Zhou, X.F., Wan, J., Zhang, T., Yang, B., et al., 2014. Pestalols A E, new alkenyl phenol and benzaldehyde derivatives from endophytic fungus Pestalotiopsis sp. acbc2 isolated from the chinese mangrove plant Aegiceras corniculatum. The Journal of Antibiotics 67, 451. € ller, W.E., Kalscheuer, R., Lin, W., et al., Umeokoli, B.O., Ebrahim, W., El-Neketi, M., Mu 2019. A new depsidone derivative from mangrove sediment derived fungus Lasiodiplodia theobromae. Natural Product Research 33(15), 2215–2222. https://doi.org/ 10.1080/14786419.2018.1496430. Volkmann-Kohlmeyer, B., Kohlmeyer, J., 1993. Biogeographic observations on pacific marine fungi. Mycologia 85, 337–346. Wang, C., Wang, J., Huang, Y., Chen, H., Li, Y., Zhong, L., Chen, Y., et al., 2013a. Antimycobacterial activity of marine fungus-derived 4-deoxybostrycin and nigrosporin. Molecules 18, 1728–1740. Wang, K.W., Wang, S.W., Wu, B., Wei, J.G., 2014a. Bioactive natural compounds from the mangrove endophytic fungi. Mini-Reviews in Medicinal Chemistry 14 (4), 370–391. Wang, J.F., Liang, R., Liao, S.R., Yang, B., Tu, Z.C., Lin, X.P., et al., 2017. Vaccinols J S, ten new salicyloid derivatives from the marine mangrove-derived endophytic fungus Pestalotiopsis vaccinii. Fitoterapia 120, 164–170. Wang, J., Ding, W., Li, C., Huang, S., She, Z., Lin, Y., 2013b. A new polysubstituted benzaldehyde from the co-culture broth of two marine fungi (Strains nos. E33 and K38). Chemistry of Natural Compounds 49, 799–802. Wang, J., Ding, W., Wang, R., Du, Y., Liu, H., Kong, X., et al., 2015. Identification and bioactivity of compounds from the mangrove endophytic fungus Alternaria sp. Marine Drugs 13, 4492–4504. Wang, J., Wei, X., Lu, X., Xu, F., Wan, J., Lin, X., et al., 2014b. Eight new polyketide metabolites from the fungus Pestalotiopsis vaccinii endogenous with the mangrove plant Kandelia candel (L.) druce. Tetrahedron 70, 9695–9701. Wang, P., Yu, J.H., Zhu, K., Wang, Y., Cheng, Z.Q., Jiang, C.S., et al., 2018. Phenolic bisabolane sesquiterpenoids from a thai mangrove endophytic fungus Aspergillus sp. xy02. Fitoterapia 127, 322–327.

[m5G;February 1, 2020;1:29] 27

Waqas, M., Khan, A.L., Hamayun, M., Shahzad, R., Kang, S.M., Kim, J.G., et al., 2015. Endophytic fungi promote plant growth and mitigate the adverse effects of stem rot: an example of Penicillium citrinum and Aspergillus terreus. Journal of Plant Interactions 10, 280–287. Wu, Z., Chen, J., Zhang, X., Chen, Z., Li, T., She, Z., et al., 2019. Four new isocoumarins and a new natural tryptamine with antifungal activities from a mangrove endophytic fungus Botryosphaeria ramosa L29. Marine Drugs 17, 88. Xia, G., Li, J., Li, H., Long, Y., Lin, S.E., Lu, Y., et al., 2014. Alterporriol-type dimers from the mangrove endophytic fungus, Alternaria sp.(SK11), and their mptpb inhibitions. Marine Drugs 12, 2953–2969. Xiao, Z.E., Lin, S.E., Tan, C., Lu, Y., He, L., Huang, X., et al., 2015. Asperlones A and B, dinaphthalenone derivatives from a mangrove endophytic fungus Aspergillus sp. 16-5C. Marine Drugs 13, 366–378. Xie, J., Wu, Y.Y., Zhang, T.Y., Zhang, M.Y., Zhu, W.W., Gullen, E.A., et al., 2017. New and bioactive natural products from an endophyte of Panax notoginseng. RSC Advances 7, 38100–38109. Xu, J., 2015. Bioactive natural products derived from mangrove-associated microbes. RSC Advances 5, 841–892. Xu, R., Li, X.-M., Wang, B.-G., 2016. Penicisimpins A- C, three new dihydroisocoumarins from Penicillium simplicissimum MA-332, a marine fungus derived from the rhizosphere of the mangrove plant Bruguiera sexangula var. rhynchopetala. Phytochemistry Letters 17, 114–118. Xu, Z., Wu, X., Li, G., Feng, Z., Xu, J., 2018. Pestalotiopisorin B, a new isocoumarin derivative from the mangrove endophytic fungus Pestalotiopsis sp. HHL101. Natural Product Research 1–6. Yang, S.Q., Li, X.M., Xu, G.M., Li, X., An, C.Y., Wang, B.G., 2018. Antibacterial anthraquinone derivatives isolated from a mangrove-derived endophytic fungus Aspergillus nidulans by ethanol stress strategy. the journal of antibiotics, 1. The Journal of Antibiotics 71, 778–784. Yu, G., Zhou, G., Zhu, M., Wang, W., Zhu, T., Gu, Q., et al., 2015. Neosartoryadins a and B, fumiquinazoline alkaloids from a mangrove-derived fungus Neosartorya udagawae HDN13-313. Organic Letters 18, 244–247. Yuan, J., Sun, K., Deng-Wang, M.-Y., Dai, C.-C., 2016. The mechanism of ethylene signaling induced by endophytic fungus Gilmaniella sp. AL12 mediating sesquiterpenoids biosynthesis in Atractylodes lancea. Frontiers in Plant Science 7, 361. Zhang, M., Li, N., Chen, R., Zou, J., Wang, C., Dai, J., 2014a. Two terpenoids and a polyketide from the endophytic fungus Trichoderma sp. Xy24 isolated from mangrove plant Xylocarpus granatum. Journal of Chinese Pharmaceutical Sciences 23, 424. Zhang, W., Xu, L., Yang, L., Huang, Y., Li, S., Shen, Y., 2014b. Phomopsidone A, a novel depsidone metabolite from the mangrove endophytic fungus Phomopsis sp. A123. Fitoterapia 96, 146–151. Zheng, C.J., Huang, G.L., Xu, Y., Song, X.M., Yao, J., Liu, H., et al., 2016. A new benzopyrans derivatives from a mangrove-derived fungus Penicillium citrinum from the south china sea. Natural Product Research 30, 821–825. Zheng, C.J., Liao, H.X., Mei, R.Q., Huang, G.L., Yang, L.J., Zhou, X.M., et al., 2018. Two new benzophenones and one new natural amide alkaloid isolated from a mangrovederived fungus Penicillium citrinum. Natural Product Research 33 (8), 1127–1134. https://doi.org/10.1080/14786419.2018.1460832. Zhou, X.M., Zheng, C.J., Chen, G.Y., Song, X.P., Han, C.R., Tang, X.Z., et al., 2015. Two new stemphol sulfates from the mangrove endophytic fungus Stemphylium sp. 33231. The Journal of Antibiotics 68, 501–503. Zhou, X.M., Zheng, C.J., Song, X.P., Han, C.R., Chen, W.H., Chen, G.Y., 2014. Antibacterial a-pyrone derivatives from a mangrove-derived fungus Stemphylium sp. 33231 from the south china sea. The Journal of Antibiotics 67, 401–403. Zhu, F., Chen, G., Chen, X., Huang, M., Wan, X., 2011. Aspergicin, a new antibacterial alkaloid produced by mixed fermentation of two marine-derived mangrove epiphytic fungi. Chemistry of Natural Compounds 47 (5), 767–769. Zhu, X., Zhong, Y., Xie, Z., Wu, M., Hu, Z., Ding, W., et al., 2018. Fusarihexins a and B: Novel cyclic hexadepsipeptides from the mangrove endophytic fungus Fusarium sp. R5 with antifungal activities. Planta Medica 84, 1355–1362. Zhu, X., Zhou, D., Liang, F., Wu, Z., She, Z., Li, C., 2017. Penochalasin K, a new unusual chaetoglobosin from the mangrove endophytic fungus Penicillium chrysogenum V11 and its effective semi-synthesis. Fitoterapia 123, 23–28. Zin, W.W.M., Buttachon, S., Dethoup, T., Pereira, J.A., Gales, L., Inacio, A., et al., 2017. Antibacterial and antibiofilm activities of the metabolites isolated from the culture of the mangrove-derived endophytic fungus Eurotium chevalieri kufa 0006. Phytochemistry 141, 86–97.

Please cite this article as: S.K. Deshmukh et al., Anti-infectives from mangrove endophytic fungi, South African Journal of Botany (2020), https://doi.org/10.1016/j.sajb.2020.01.006