Macromolecular agents with antimicrobial potentialities: A drive to combat antimicrobial resistance

International Journal of Biological Macromolecules 103 (2017) 554–574

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International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac

Macromolecular agents with antimicrobial potentialities: A drive to combat antimicrobial resistance Muhammad Bilal a,∗ , Tahir Rasheed b , Hafiz M.N. Iqbal c,∗ , Hongbo Hu a , Wei Wang a , Xuehong Zhang a a

State Key Laboratory of Microbial Metabolism, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China The School of Chemistry & Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai, 200240, China c School of Engineering and Science, Tecnologico de Monterrey, Campus Monterrey, Ave. Eugenio Garza Sada 2501, Monterrey, N.L., CP 64849, Mexico b

a r t i c l e

i n f o

Article history: Received 1 March 2017 Received in revised form 23 April 2017 Accepted 15 May 2017 Available online 19 May 2017 Keywords: Antimicrobial resistance Plant-derived antimicrobial Metal-based antimicrobial Macromolecules Nanotechnology-assisted antimicrobials

a b s t r a c t In recent years, the antimicrobial resistance (AMR) or multidrug resistance (MDR) has become a serious health concern and major challenging issue, worldwide. After decades of negligence, the AMR has now captured global attention. The increasing number of antibiotic-resistant strains has threatened the achievements of science and medicine since it inactivates conventional antimicrobial therapeutics. Scientists are trying to respond to AMR/MDR threat by exploring innovative platforms and new therapeutic strategies to tackle infections from these resistant strains and bypass treatment limitations related to these pathologies. The present review focuses on the utilization of bio-inspired novel constructs and their potential applications as novel antimicrobial agents. The first part of the review describes plantbased biological macromolecules containing an immense variety of secondary metabolites, which could be potentially used as alternative strategies to combat antimicrobial resistance. The second part discusses the potential of metal-based macromolecules as effective antimicrobial platforms for preventing infections from resistant strains. The third part comprehensively elucidates how nanoparticles, in particular, metal-integrated nanoparticles can overcome this AMR or MDR issue. Towards the end, information is given with critical concluding remarks, gaps, and finally envisioned with future considerations. © 2017 Elsevier B.V. All rights reserved.

Contents 1. 2.

3.

Problem and opportunities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 Plant-based antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 2.1. Historical use of plants as antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 2.2. Present-day use of plants as antimicrobial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556 2.3. Mechanism of antimicrobial action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556 2.3.1. Antibacterial potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556 2.3.2. Antifungal potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556 Metal-based antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557 3.1. Mechanisms of action of metal-assisted antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557 3.2. Metal-based antimicrobial macromolecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 3.2.1. Copper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 3.2.2. Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 3.2.3. Platinum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 3.2.4. Ruthenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 3.2.5. Silver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568

∗ Corresponding authors. E-mail addresses: [email protected] (M. Bilal), hafi[email protected], hafi[email protected] (H.M.N. Iqbal). http://dx.doi.org/10.1016/j.ijbiomac.2017.05.071 0141-8130/© 2017 Elsevier B.V. All rights reserved.

M. Bilal et al. / International Journal of Biological Macromolecules 103 (2017) 554–574

4.

5.

555

Nanotechnology-based antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 4.1. Nanoparticles against drug-resistant bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 4.2. Metallic nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569 Concluding remarks and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572

1. Problem and opportunities In the last decade, an inevitably increases both in the proportion and numbers of bacterial pathogens conferring multidrug resistance (MDR) to various antibacterial agents has been witnessed. Key organizations including the US Centers for Disease Control and Prevention (CDC), the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) are contemplating MDR bacterial-caused infections as a budding disease and a major health dilemma, across the globe [1]. Regardless of the manifestation of antibacterial agents, the rise and spread of resistant pathogens may take place, either by mutations or the acquisition of mobile genetic elements carrying resistance genes. The acquaintance, abuse, and misuse of antibacterial agents are the ultimate driving forces for the increasing rates of the emergence of resistant microorganisms. At contemporary, the antimicrobial resistance has developed a global health threat compelling the coordinated strategies of different stakeholders (i.e. policymakers, the scientific community, regulatory organizations, public health authorities, therapeutic companies) [1]. The organizations mentioned above are developing a multifaceted approach to combating antimicrobial resistance at its very root. According to the WHO report, infectious diseases are the third most significant cause of mortality worldwide. Several strains including Escherichia coli and Klebsiella pneumoniae (??-lactamase-producers), Enterobacteriaceae and Pseudomonas aeruginosa (carbapenem-resistant), Staphylococcus aureus (hospital acquired methicillin resistant), and Enterococcus (vancomycin resistant) have been recognized as most terrible pathogens, to which effective remedies are urgently required [2]. The therapeutic options for these microorganisms are extremely inadequate and Clinicians are enforced to prescribe expensive drugs with significant side effects [3]. It is crucial to discover some alternatives that can potentially be effective in the treatment of these infectious diseases. Effectiveness of phytoconstituents commonly known as phytochemicals/phytobiotics such as alkaloids, tannins and phenolic etc. in herbal plants has drawn considerable interest for antimicrobial therapy, since they have shown potential for the treatment of many diseases [4–8]. Approximately 80% of the world’s population relies on traditional medicine for their fundamental healthcare requirements. With ever-increasing scientific and social awareness of diseases caused by various microorganisms, attention is now being focused towards alternative approaches to control or limit such deadly infections. Many materials with antimicrobial activities are attracting the considerable attention of both academia and industry, especially in the biomedical, and other health-related areas of the modern world [9–13]. Owing to the growing realization and demands of legislative authorities, the manufacture, to reduce bacterial population in healthcare facilities and possibly to cut pathogenic infections, search for natural sources and engineering novel anti-microbial active constructs is considered to be a potential solution to such a problematic issue. Much research is underway around the world on the development of ‘greener’ technologies with fewer side effects. There has been a growing search for new high-performance products for multipurpose applications

in biotechnology at large and biomedical, pharmaceutical and cosmeceutical in particular [14]. One area that has received limited attention so far, but that will gain in importance as naturally conferring antimicrobial agents from natural plant-based sources and the incorporation of such novel agents, to provide an antibacterial effect on contact of that material with the target bacterium. There are clear industrial and biotechnological requests for materials that are loaded with natural agents that can quickly prevent deleterious microbial action following contamination events [10–13,15,16]. Various biological approaches using biological molecules derived from plant sources in the form of extracts displayed superiority over chemical and biological methods. These plant-based biological molecules undergo highly controlled assemblage to maintain the suitable size of nanoparticles. This critical review mainly focuses on the utilization of vast diversity of plants in the bio-inspired synthesis of novel constructs as well as their potential applications as novel antimicrobial agents. The first part of the review describes bioactive molecules from plants and their antimicrobial mechanism of action against various microbial strains. The second part is focused on various metal-based macromolecules and their antimicrobial potentialities. In the third part, nanoparticles formulations from the nanotechnology theme are presented along with their antimicrobial activities. Towards the end, information is given with critical concluding remarks, gaps, and finally envisioned with future considerations. 2. Plant-based antimicrobials Traditionally used medicinal and industrial crop plants produce a diverse array of bioactive compounds that have pharmacological or toxicological effects on the health of human and animals. Most of these compounds are constitutive, existing in their biologically active forms in healthy plants while some others (such as cyanogenic glycosides and glucosinolates) occur as inactive precursors and are triggered in response to pathogen attack or tissue damage. Though the essential nutrients elicit pharmacological or toxicological effects at their high dosages (e.g. vitamins and minerals), plants nutrients are, in general, not included regarding bioactive compounds. 2.1. Historical use of plants as antimicrobials Since antiquity, plants have provided a source of inspiration for developing novel drug compounds, as plant-derived medicines have largely contributed to human health and well-being. Undeniably, plants showed two-fold role in the development of new drugs; first: they may become the base for the natural development of new drugs, or; second: a phytomedicine to be employed for the treatment of infectious diseases. Numerous illustrations of plantderived compounds as anti-infective drugs have been presented. The isoquinoline alkaloid emetine obtained from the Cephaelis ipecacuanha has been used for many years as an amoebicidal drug and the treatment of abscesses due to the spread of Escherichia histolytica infections. Similarly, Cinchona plant-originated quinine has a long history of therapeutic use in the treatment of malaria and to relieve nocturnal leg cramps. Apart from anti-infective, higher

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plants-derived compounds, e.g., the anti-leukaemic alkaloids, vinblatine and vincristine, obtained from the Madagascan periwinkle (Catharanthus roseus syn. Vinca roseus) have made significant contributions in the areas of cancer therapies [17]. 2.2. Present-day use of plants as antimicrobial It is estimated that currently, plant materials are present in, or have provided the models for 50% Western drugs. Many commercially established drugs incorporated in the modern medicine were initially used in crude form in traditional or folk healing practices, or for other purposes that suggested potentially useful biological activity. Interestingly, the principal advantages of employing plant-originated medicines are that they are relatively safer and affordable than synthetic alternatives, offering profound therapeutic benefits as well as economic benefits. There has been a renewed interest, across the globe, in natural products. The potential for developing antimicrobials into medicines appears rewarding, from both the perspective of drug development and the point of view of phytomedicines. The immediate source of financial benefit from plants based antimicrobials is from the herbal products market Ciocan and Bara, 2007. The beneficial remedial effects of plant materials characteristically consequence from the mixtures of secondary products present in the plant. These compounds in plants are mostly secondary metabolites such as alkaloids, steroids, tannins, and phenolic compounds, and can be classified based on their chemical structure, which also influences their antimicrobial property. The plant’s secondary products may exert their beneficial medicinal actions on humans by resembling endogenous metabolites, ligands, hormones, signaling molecules or neurotransmitters. Table 1 shows the most vigorous bioactive compounds from medicinal plants (Unpublished). A comprehensive screening of plants for active chemicals is as important as the screening of ethnobotanically targeted species. The ethno-medicinal information of about sixtythree plant species from district Swabi, Pakistan belonging to thirty-six families is presented in Table 2 [18]. 2.3. Mechanism of antimicrobial action The increasing challenges regarding the application of chemosynthetic antibiotics, such as antimicrobial resistance, environmental anxieties, and carcinogenicity, are of worldwide concern. Extensive research has been focused in the last several years to allocate the antimicrobial characteristics of the herbal plant infusions and essential oils against various investigated pathogenic and non-pathogenic agents [51]. Different modes of functions have been proposed for the antimicrobial potentials of the essential oils available in medicinal plants. Due to the presence of numerous compounds and wide chemical profiling of the extracts and essential oils components, it is likely that one solitary mechanism does not cause antimicrobial potentiality; but several mechanisms of antimicrobial functions are considered at the cellular level. Concisely, some major mechanisms of antimicrobial activities of plant extract and essential oils as are summarized by Djilani and Dicko [52]. 1) Decomposition of cytoplasmic membrane. 2) Accretion with proteins placed on membrane (for example ATPase). 3) Disturbance and inactivation of the operation of outer membrane of gram-negative bacteria by abandoning lipopolysaccharides. 4) Fluctuation of the proton engine force of the cells with permeance of ions. 5) Coagulation of cell inner contents.

6) Prevention of enzyme generation. 2.3.1. Antibacterial potential The antibacterial activities of medicinal plant extracts and essential oil predominantly occur on the structures and cellular membrane. It is reported that essential oils, including eugenol, ␣terpinol, and ␥-terpinene have expressed antibacterial capabilities against all types of bacteria with diverse membrane structures by the infraction of the cell septum. The gram-negative bacteria (GNB) are more resilient towards the action of bioactive compounds as compared to gram-positive bacteria (GPB) [53]. This weak antibacterial activity of herbal infusions against the GNB is attributed to the presence of one further outer septum that reduced the penetration rate of hydrophobic compounds into the cells including essential oils, and other compounds with antimicrobial activities. Nonetheless, the consequences of some researchers have shown similar capability for both GNB as well as GPB. The organic extracts, such as ethyl acetate, and methanol have been recognized to ensure better antimicrobial potentials contrasted with aqueous infusions, since being organic, they dissolve more bioactive blends, resulting in the dissemination of greater level of active antimicrobial factors [54]. The antimicrobial activity of plant extracts and oils has appraised the foundation of diverse applications, including medicine, raw food processing and preservation, pharmaceutical and natural therapies. A list of ethno-medicinal plants employed for the treatment of antimicrobial diseases is summarized in Table 3. In their study, Cushnie and Lamb [70] stated that flavonoids possess capabilities to form complexes with extracellular soluble protein and bacterial cells; Catechins also posed antibacterial potential via DNA gyrase prohibition operations Gradisar et al., 2007. It is also worth noting that catechins could enhance the sensitivity of bacterial antibiotic resistance to other kinds of antibiotics, such as tetracycline and ˇ-lactam, by rehabilitating the repressors sensitivity [71]. 2.3.2. Antifungal potential The tracking of fungal infections poses serious dilemmas probably due to a limitation in the accessibility of anti-fungal factors with profound inhibition potentials and resistance properties. The exploration of antifungal factors, such as extracts of medicinal plants, with marked potentials, is indispensable to be applied in the suppression of the strains exhibiting persistence to the available antifungal medicines. The plant’s extract is based antifungal properties might be imputed to essential oils, polyphenolic compounds and oxygenated monoterpenes triggering cell membrane damage by increasing leakage of inner cellular contents outside, and eventually, microorganism death [72]. The mechanisms of antifungal actions are consonant to those described above for bacteria, including irreversible trauma to the cell septum, exuding and coagulation of cellular interior materials. In some instances, the mixture of various essential oils and extracts might demonstrate pronounced antimicrobial potentiality than individual ones possibly due to synergistic phenomena. Salem et al. [54] examined the antibacterial potential of Callistemon viminalis leave extracts in different solvents, including methanol, chloroform, n-butanol, ethyl acetate extract and aqueous fractions at about 2 mg/ml. Amongst the solvents tested, ethyl acetate fraction displayed the highest inhibition potentials against Escherichia coli and the lowest activity for Serratia marcescens. Other solvents such as ethanol and methanol extracts also acted as potent antibacterial factors against the tested bacteria’s growth. Essential oils also expressed remarkable potentials towards bacteria’s strains. An estimated 250,000–500,000 plant species have been investigated around the globe to date. Nevertheless, the only 1/10th of these plants are explored for obtaining bioactive compounds. The major bioactive compounds which have been acknowledged

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Table 1 Bioactive compounds obtained from medicinal plants. Component name

Neutral mass Observed Observed (Da) neutral mass m/z (Da)

Mass error (mDa)

Mass error (ppm)

Observed RT Detector (min) counts

Response

Adducts

1-O-Caffeoyl-␤-d-glucopyranoside Furoic acid 5R-5-Hydroxymethyl-2(3H)-furanone 5␣-Androstane-3␤,17␤-diol 9,16-Dioxyhydroxy-10,12,14-triene-18 carbonic acid Catechol Luteolin-7-O-[␤-dapiofuranosyl(1 → 6)]␤-dglucopyranoside Luteolin-7-O-glucuronide ethyl ester Methyl-5-O-caffeoylquinate Coumaric acid Quercetin-3-gentiobioside-7-glucoside Quercetin-3-O-(6”-O-acetyl)-␤-dglucopyranoside Quercetin-3-O-(6-O-feruloyl-␤-dglucopyr-anosyl)-(1 → 2)-␤-d-galactopyranosyl-(1 → 2)-␤-dglucopyranoside

342.09508 112.01604 114.03169 292.24023 310.21441

342.0964 112.0159 114.0318 292.2388 310.2121

341.0891 111.0086 113.0245 291.2315 309.2048

1.3 −0.2 0.1 −1.4 −2.3

3.7 −1.7 1.1 −4.8 −7.4

3.25 0.92 4.28 7.31 6.82

67 185 375 526 163

67 185 375 526 163

−H −H −H −H −H

110.03678 580.14282

110.0373 580.1438

155.0355 625.142

0.5 1

3.5 1.6

12.46 2.84

345 39

345 39

+HCOO +HCOO

490.11113 368.11073 164.04734 788.20112 506.10604

490.1074 368.1093 164.0467 788.1975 506.1044

535.1056 367.102 163.0394 787.1902 505.0971

−3.7 −1.5 −0.7 −3.7 −1.7

−6.9 −4 −4.3 −4.6 −3.3

3.74 2.73 3.29 2.49 4.22

4774 30 3858 3267 297

3513 30 3398 2183 241

+HCOO −H −H −H −H

964.24847

964.2467

963.2394

−1.8

−1.9

2.92

4087

2486

−H

as antimicrobial agents are polyphenols, polypeptides, terpenoids, flavonoids, isothiocyanates, tannins, lectins, and alkaloids, or also oxygen substituted formatives [5,6]. Regardless of many studies carried out on the functional mechanism of antimicrobial ingredients of medicinal plant extracts, the exact principle of these compounds is still unclear necessitating further investigations. Table 4 illustrates some major plant-based antimicrobial compounds, their structures, and mechanisms of action. The projected compound’s quantity available in herbaceous plants extracts varied depending on a variety of plant, geographical origin, plant part used, age, methods of extraction, preparation, wrapping and keeping conditions of products. Identification and evaluation of biologically active compounds for the determination of pathogens, and to ensure the consumer’s safety is a challenge for further studies. It has been demonstrated that the antimicrobial properties of herbal plants are due to the availability of coumarin, scopoletin and umbelliferone components [18]. 3. Metal-based antimicrobials It is reported that metal-based macromolecules demonstrate their function using diversified mechanisms. Inarguably, the metals simultaneously interact with intracellular ligands such as enzymes and proteins catalyzing intracellular biochemical processes, thus imitating a greater challenge to drug-resistant strains. Recent advances in organic chemistry together with macromolecular chemistry have made it possible to precisely insert metals into the macromolecular scaffold permitting excellent control over the architecture of the macromolecule, which in turn tunes the properties. Remarkable achievements have provided insights into the design of metal-based antimicrobial macromolecules with incredible antimicrobial activity against resistant strains [77]. 3.1. Mechanisms of action of metal-assisted antimicrobials The mechanism of action of metal-assisted antimicrobial agents is predominantly based on selective interference in cellular processes, and relying on the physicochemical properties of the metal and its associated ligands. Several discoveries in this field demonstrate that metal-based antimicrobials disrupt and kill microbial cells by inducing oxidative stress, causing protein dysfunction, or interfering cell membrane [78–82]. Metal-based antimicrobial

agents can posture multiple mechanisms of action, acting synergistically to pose a strong challenge to various drug-resistant microbes (Fig. 1). Unarguably, membrane-disrupting antimicrobial agents act strongly against resistant strains, and as a consequence commendably alleviate the progression of resistance. It is reasonable to postulate that the multiple mechanisms of action take part to the effectiveness of these metal-assisted antimicrobial agents against the drug-resistant strain [82]. Another mechanism for fighting resistance implicates ligandexchange reactions of organometallic compounds such as carbon monoxide-releasing molecules (CORMs). Though carbon monoxide (CO) is detrimental due to its strong affinity for hemoglobin; it has also been recognized as therapeutic since mammalian cells generate a small quantity of CO performing essential intracellular functions. CO reacts with transition metals to form transition-metal carbonyl CORM, which can instantaneously exchange their CO with a solvent molecule or can releases the CO upon activation by an external trigger such as light energy [84]. CORMs are far more toxic to microorganisms than free CO. Under both aerobic and anaerobic culturing conditions, Nobre et al. [85] evaluated the activity of a series of CORMs on the growth of E. coli and found the effective reduction in the viability of anaerobically cultured E. coli as compared to the anaerobically cultured counterpart. The elevated activity of CORMs on the anaerobically cultured E. coli might be ascribed to the preferential binding of CO to the ferrous form of heme proteins. The CORMs displayed large spectrum potentiality in suppressing the growth of Gram-positive S. aureus and Gram-negative E. coli. The ability to release CO is essential to the antimicrobial activity of CORMs, and the presence of CO scavenger hemoglobin could deactivate the CORMs activity. Again, CORMs release CO intracellularly after accumulating within the cell [85]. The antimicrobial activity of CORMs may also exploit an ROStriggered oxidative stress pathway [86]. A recent study of Nobre et al. [154] involving seven CORMs corroborates the intracellular generation of ROS in E. coli. With minor exceptions, the bactericidal activity positively coincided with a generation of ROS. Overall, the results suggest that CORMs-derived ROS contributes to antimicrobial activity. Oxidative stress induced microbial disruption remains controversial [87–91]; nevertheless, it is a broadly accepted mechanism of metal-assisted antimicrobial activity [92–94,90]. Although oxidative stress is induced in the absence of ROS [95–97], increasing evidence has supported the ROS-

558 Table 2 Chemical constituents and therapeutic uses of medicinal plants collected from the District Swabi, Pakistan (Reproduced from Khalid et al. [18]; an open access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/)). Local Name in Pushto

Family

Chemical constituents

Part used

Uses

Amaranthus spinosus L

Chalvere

Amaranthaceae

Sterols, Leaves and stems contain hentriacontane, alpha-spinasterol and the lysine is found in higher amount a protein unit. Beside this eight other essential amino are also found [19].

Pollen grain and roots

Extraction from the pollen grains is used to treat rhinitis, asthma. Dried roots are good remedy for menorrhea.

Acacia arabica L.

Kikar

Fabaceae

Gum is rich in arabinose, galactose and rhamnose. These are the sugar content and acids include 4methoxyglucuronic acid and glucuronic acid [20].

Gum

Gum is applied on burns, sore and taken orally for inflammation of intestinal mucosa.

Albizia lebbeck L. Benth.

Siris tree

Fabaceae

Albigenic acid, acacic acid, flavonoids, tri-terpenoids, tri-terpenoid saponins, albigenin and oleanolic acid [21].

Bark

The bark is used for inflammation, pectoral and lungs problems.

Allium cepa L.

Pyaz

Alliaceae

The composition of volatile oil includes flavonoids, allicin, phenolic acids, diarrhoea containing compounds.

Whole plant

Anticoagulant, antisclerotic, Antibiotic, antibacterial.

Achyranthes aspera L.

Geshe

Amaranthaceae

Ecdysone, polypodineA, achyranthine, Saponin, Eedysterone and oleanolic acid.

Fruiting body

Laxative, carminative, stomachic, and effective in the treatment of vomiting.

Allium sativum L.

Uga

Alliaceae

Magnesium, Vitamin A, volatile oil, Vitamin C and different Amino acids (Agharkar, 1991).

Bulb

Bacteriostatic, Antibiotic, Hypotensive, anthelmintic, fungicide, hypoglycemic, antithrombic

Aloe vera (L.) Burm.f

Aloe vera

Asphodelaceae

C-glycosides, anthraquinones, anthraquinone, acetylated mannans, polymannans and anthrones

Leaves

Effective for treating wrinkles, stretch marks and pigmentation on skin.

Aerva javanica (Burm.f.) Shult

Spen botey

Amaranthaceae

Glucosides, ascorbic acid, beta-amyrin, beta sitosterol, sitosterol and kaempferol is the most abundant flavonoids.

Fruiting body

Diuretic, Anti-inflammatory, insecticidal anticalculus,

Berberis lyceum L.

Zyar large

Berberidaceae

Tannins, umbellatine, Alkaloids, berbamine and starch.

Stem and roots

For broken bones, wounds, gonorrhea, curative piles, unhealthy ulcers.

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Botanical name

Table 2 (Continued) Local Name in Pushto

Family

Chemical constituents

Part used

Uses

Bauhinia variegate L.

Kachnar

Fabaceae

Isoquercitin, tannin, astragalin, glucose, gum, Seeds contain 16% potassium and varied amount of fatty acids [22].

Bark and roots

Increase red blood cells, carminative astringent, Roots are laxative and flower extraction is blood cleanser

Chenopodium album L.

Larmay sarmay sag

Amaranthaceae

Ascaridole, cryptomeridiol, 8% aponins. Its seeds contain ascaridole [23].

Young shoot leaves

Antiscorbutic, Laxative, anthelmintic clean the body from hookworms and roundworm, blood-purifier

Cyperus rotundus L.

Dela

Cyperaceae

Phosphorus, alkaloids, carbonates, aromatic oil and vitamins

Rhizome

Dried rhizome is used for skin disorders and indigestion.

Cannabis sativa L.

Bhang

Cannabaceae

Tetrahydrocannabinol (THC), cannabispirans, alkaloids and Cnnabinoids [24].

Roots

Its roots are effective for tumor treatment. analgesic, stomachic, narcotic, sedative

Carum carvi L.

Tora Zeera

Apiaceae

Flavonoids, limoline, quercetin, calcium oxalate. Limoline and carvone [25].

Seeds

Seeds are used to treat loss of appetite and colic, stomach problems

Cichorium intybus L.

kashni

Asteraceae

Scopoletin, lactucopicrin, esculin, chicoriin, Inulin, sesquiterpene, coumarins, pyromucic and lactones.

Leaves

Tea prepared from its fresh leaves is useful for liver disorder, especially during hepatitis treatment and for loss of appetite

Curcuma longa L.

Curcaman

Zingiberaceae

Resin, curcumin, starch and mono desmethoxycurcumin. Rhizome is rich with curcuminoids

Rhizome

Antibacterial agent for cuts burns and bruises.

Cuscuta reflexa L.

Par sevsaha.

Cuscutaceae

Cuscutatin, kaempferol, beta-sitosterol, luteolin, mangiferin and bergenin (Löffler, Sahm, Wray, Czygan, & Proksch, 1995).

Delicate stem

Blood purifier, good for brain, purgative and fever.

Calotropis procera L.

Spen botay.

Apocynaceae

Cardenolide, evanidin 3-rhamnoglucosid flower component, Beta-amyrin, proceragenin. Bark contains benzolisolineolone and benzoyllineolone [26].

Leaves

Depurative, expectorant, Febrifuge, laxative and anthelmintic.

Cuminum cyminum L.

Zankay

Apiaceae

Stable oils, phosphorus, minerals, cumaldehyde, iron, stach and protein. Its good taste is due to cumin [27].

Seeds

Effective against stomach disorders, antispasmodic carminative, diarrhea

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Botanical name

559

Table 2 (Continued) Family

Chemical constituents

Part used

Uses

Coriandrum sativum L.

Dhanyal

Brassicaceae

Coumarins, chlorogenic, terpinine, linalool, volatile oil, caffeic.

Fresh leaves

Tea is prepared and administered in conditions of indigestion, cold, cough and asthma

Convolvulus arvensis

Prevatay

Convolvulaceae

Resin, cuscohygrine, meesculetin, alpha-amyrin, sterols, aerial parts are rich with n-alkanols and n-alkanes [28].

Fresh shoot

laxative, cholagoguem and purgative

Capsicum annuum L.

Marchakey

Solanaceae

Saponins, Capsaicin, flavonoids, carotenoids, Capsaicin and seeds contain capsicidins [29].

Fruiting body

Carminative, Stimulate adrenal glands to yield more corticosteroids,

Datura stramonium L.

Daltoora

Solanaceae

Withanolides, coumarins, flavonoids and alkaloids like tropane and anticholinergic

Flowers and seeds

Used in Asthma, anticholinergic, Spasmolytic, nervous system sedative

Euphorbia helioscopia L.

Peryan dolay

Euphorbiaceae

Phasin, saponin, volatile oil and Nonhaemolytic

Roots

Roots are used as anthelminthic and to treat constipation

Eugenia jambolana (L.) Skeels.

Jaman

Myrtaceae

betulenic acid, oxalic acid, diglycosides, fats, amino acids, malic acid and jamboline [30]

Fruits and leaves

Fruits are used in dysentery and leaves for gingivitis.

Eruca sativa L.

Jamama

Brassicaceae

Isothiocyanate, glucoerucin, leaves yield iso-rhamnetin, cispiperitone oxide and anthocyanins [31].

Fruits

Antiscorbutic, stomachic, diuretic, rubefacient, seeds are antiseptic.

Fagonia arabica L.

Azghake

Zygophyllaceae

Fagonone, nahagenin, sapogenin, oleanolic acid. diterpenes, fagonone and its derivatives, flavonoids [32].

Shoot

Antiseptic, astringent, blood-cleaner and febrifuge

Fumaria parviflora Lam.

Papra, shaahtaraa.

Quercetin glycosides, flavonoids, Isoquinoline, protopine, cryptopine and sanguinarine.

Shoot

Laxative, detoxifying, diaphoretic

Ficus carica L.

Enzar

Fumariaceae

Leaves contain oleanolic acid and calotropenyl acetate. Fruits major constituents are psoralen, apogenin, Bergapten.

Fruit

Pulp of fruit is analgesic and reduces inflammation.

Foeniculum vulgare Mill.

Kaga, Sonf

Apiaceae

Flavonoids, bergapten, methylchavicol, volatile oil anethole, fenchone and coumarins [33]

Seeds

Emmenagogu, carminative, antispasmodic, stomachic, galactagogue

Juglans regia L.

Dandasa, Akor

Juglandaceae

Eugenol, protopine, saponins, triterpene, diterpene and Monoterpenes. Bark contains levulinic and stigmasterol [33].

Young brances and bark

Is used to clean the teeth and to reduce frequent urination.

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Local Name in Pushto

560

Botanical name

Table 2 (Continued) Local Name in Pushto

Family

Chemical constituents

Part used

Uses

Litchi chinensis Sonn

Litchi

Sapindaceae

Lactic, fumaric, malic, citric, malonic, succinic, friedelin, phosphoric, glutaric acids. Bark contains melianol, diosmetin and minerals [34].

Fruits

Gastralgia, Relieve coughing, glands infection and tumors

Lepidium sativum L.

Alum

Apiaceae

Alkaloids, D-glacturonic, sinapin, glucotropaeolin, sinapic acid, uric acid and mucilaginous matter five percent [35].

Seeds

To treat diarrhea especially in children, leprosy, dysentery

Momordica charantia Sonn.

Karelaa.

Cucurbitaceae

Saponins, palmitic, phenolic constituents, Fruits are rich with Galactouronic acid [36].

Fruits

leaf tea is employed for diabetes, colic, sores and wounds, infections and parasites

Mentha longifolia (L.) Huds

Velanay

Lamiaceae

Luteolin, cispiperitoneoxiden, anethole, piperitone, sinapic acid, volatile oil and antioxidants.

Whole shoot portion

antiseptic, and used in disorders of alimentary canal

Morus nigra L.

Thot siyah

Moraceae

Sugar, rutin, pectin, fruit acids others are citric acid, malic, ascorbic acid [37]. Fumaramine and flavonoids.

Fruits

Effective in throat and respiratory canal infections

Morus alba L.

Spen thot

Moraceae

Phenolics delphinidin, glucosides, bicuculline, alkaloids, anthocyanins, artocarpin, cycloartocarpin [37].

Fruits

Sore throat, dyspepsia and melancholia

Melia azedarach L.

Bakyana

Meliaceae

Tetranortriterpenoids, quercitrin, bakayanin, lactone, bakalactone, rutin, vilasinin and salanin [38].

Gum

Gum is used in spleen enlargement and emmenagogue

Mentha spicata L.

Podina

Lamiaceae

Derivatives of caffeic acid comprise the volatile oil, diosmin, flavonoids, diosmetin and rosmarinic acid

Fresh shoot

Antiemetic, carminative, stimulant, antiseptic and antispasmodic

Mirabilis jalapa L.

Gulabasi

Nyctaginaceae

Triterpenes, glucoerucin, alpha-amyrin, ‘MAP’ Mirabilis Antiviral Protein.

Leaves

Leaves are used as a bandage on wounds. Purgative, and used for vulnerary (wound healing), aphrodisiac as well as diuretic and purgative.

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Botanical name

561

562

Table 2 (Continued) Local Name in Pushto

Family

Chemical constituents

Part used

Uses

Oxalis corniculata L.

Malhoze

Oxalidaceae

Flavonoids, saponin, isovitexin, vitexin-2, D-glucopyranoside, citric acid, malic acid and vitexin

Fresh leaves

Indigestion and diarrhea in children, dysentery

Opuntia stricta (Haw.) Haw.

Zukam

Cactaceae

Isorhamnetin, betanin, fatty oil, arbinogalactan, Polysaccharide, Flowers have constituents like glycosides of isorhamnetin and flowers having trace flavonol.

Fruits

Fruits are cooked and used as remedy for severe cough

Paeonia emodi Wall.ex Royle

Mamaikh

Paeoniaceae

Atropine, essential oil, tropane and some benzoic acid, salicylaldehyde, fixed oil, and sucrose.

Rhizome

The powder of dried rhizome is used in Pain purposes.

Papaver somniferum L.

Opium Poppy

Papaveraceae

Different alkaloids like papaverine, morphine, narcotine, codein and Capsaicin [39].

Latex and seeds

Antispasmodic, Narcotic, hypnotic, analgesic, anodyne, sedative and used to relief the pain.

Plantago lanceolata L.

Speen Ispaghul

Plantaginaceae

Silica, potassium, alpha-amyrin, mucilage, zinc, glycosides, caffeic and Tannins [40].

Seeds

Demulcent, Astringent Expectorant, having healing and soothing effect on intestine mucosal layer.

Punica granatum L.

Anar

Lythraceae

Pentunidin, punicalin, punicalagin, ellagic acid, sugar and cardenolide (Poyrazo˘glu, Gökmen, & Art␫k, 2002).

Fruits skin and bark

Grounded fruits dried bark is a quick remedy for stomach problems

Portulaca oleracea L.

Warhary

Portulacaceae

Catechol, resin, adrenaline, dopamine and beta-sitosterol [41].

Fresh shoot

Antiseptic, speed up the healing of wound, remedy for kidney and spleen problems.

Phaseolus lunatus L.

Lobya

Fabaceae

Saponins, esculetin, alkaloids and flavonoids, also give phaseolunatin, iron, sugar and protein [42].

Seeds

Astringen and used as a diet in fever

Rumex dentatus

Shulkhay

Polygonaceae

Emodin, Cryptomeridiol, flavonoids plus rutin, quercitrin, aloe, avicularin and emodin [43].

Fresh leaves

Antiseptic and generally used for skin problems

Ricinus communis L.

Aranda

Euphorbiaceae

Stearic, linoleicm, ricinoleic acid, isoquercitin, oleic and dihydroxystearic acids are also found in little amount.

Leaves

Tea of leaves is administered for lumbago.

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Botanical name

Table 2 (Continued) Local Name in Pushto

Family

Chemical constituents

Part used

Uses

Salvia moorcroftiana Wall. exBenth.

Khardug

Lamiaceae

Luteolin, volatile oil, umbellatine, flavonoids, salvigenin, diterpene, carnosolic acid, hispidulin and luteolin [44].

Fresh leaves

Used for colic, dysentery and hemorrhoids.

Solanum. Xanthocarpum L.

Mara gone

Solanaceae

Potassium nitrate, sitosterol, solanocarpidine, Solanocarpine, carpesterol, fatty acid, diosgenin and isochlorogenic acid [45].

Root

Root is an expectorant, used for cough, asthma and chest pain.

Salix tetrasperma L

Harola, Harwala

Salicaceae

Salicin, polymannans, tannin, Bark major constituents are fragilin, phenol, tannin, glycosides, salicin, salicortin, salireposide, salicase and triandrin [46].

Bark and leave

Bark is used for fever treatment and leaves for piles and rheumatism.

Solanum nigrum L.

Kachmachu

Solanaceae

Sapogenins, diosgenin, anthrones, glycosides, solasonine, tigogenin, solasodine and solasodine.

Fruits

The fruit juice has been used as an analgesic for tooth pain.

Sonchus asper (L.) Hill

Shodapay

Asteraceae

Rubber, little amount of acetic acid, alphaand, selenium, beta-lactucerols alcohol and mannitol.

Fresh shoot

Parts of the plant have been used variously to stimulate menstrual flow and stimulate fluid removal.

Silybum marianum L.

kareza

Asteraceae

Silibinin, Seeds constituents include flavanol, lignin, silybin, and vitamin C.

Seeds and flowers

Young leaves and flowering heads are consumed by diabetics. It is also used by nursing mothers to promote the production of milk.

Trigonella foenum-graecum L.

Mulhuzy

Fabaceae

Seeds essential constituents include sesquiterpenes, essential oil, Eedysterone and n-alkanes [47].

Seeds

Seeds are taken to cure loss of appetite, diarrhea, flatulence, dyspepsia and dysentery.

Tamarix aphylla (L.) Karst.

Ghaz

Tamaricaceae

Bark major component are gallic acid, dehydrodigallic acid, achyranthine, polyphenol, ellagic acid, glucoside and juglanin. polyphenol, ellagic acid, glucoside and juglanin [48].

Dried bark

Use to treat the infection of gums and teeth, rheumatism, and Jaundice.

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Botanical name

563

564

Table 2 (Continued) Local Name in Pushto

Family

Chemical constituents

Part used

Uses

Taraxacum officinale F.H. Wigg

Zyargule

Asteraceae

Roots contain Taraxacin, acrystalline, Taraxacerin, gluten and sugar [49].

Roots

Locally it is used for the treatment of blood pressure and diabetes and also used as salad

Tribulus terrestris L.

Markunday

Zygophyllaceae

Furostanol, spirostanol, allicin, glycosides, glycosides, Steroidal saponins magnesium and potassium [50].

Fruits

Fruit are diuretic, demulcent, anti-inflammatory, muscle relaxant, hypotensive

Trachyspermum copticum L.

sperkay

Apiaceae

Phenols, carvacrol, saponin, largely thymol, dehydrodigallic acid.

Seeds

Ajowan is much valued for its antispasmodic, stimulant, tonic and carminative properties.

Xanthium strumarium L.

Jeshe

Asteraceae

Xanthinin, sesquiterpene, glucuronic acidm, stizolicin lactones, solstitialin, and Xanthatin [50].

Roots

Roots are used to cure tumor. Leaves are use externally on sores

Zingiber officinale L.

Adrak

Zingiberaceae

Bisabolene, resins, zingiberene, zingiberene and zingiberol, zingiberene, zingiberol, quercetin, volitile oils “zingiberene”.

Rhizome

Stimulant, carminative and used frequently for dyspepsia, gastroparesis, slow motility symptoms, constipation, and colic.

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Botanical name

Table 3 Ethno-medicinal plants employed for the treatment of antimicrobial disease. Botanical name

Local name

Family

Part used

Extract

Organism inhibited Gram positive

Forest red gum Gotu kola Bakayan Kachmachu

Myrtaceae Umbelifers Meliaceae solanacea

Allium sativum

Uga/Garlic

Amaryllidaceae

Camellia sinensis

Shna chai/green tea

Theaceae

Leaf Whole plant Leaf and root Shoot

Methanol Acetone Methanol Ethanol

Escherichia coli Bacillus cereus Micrococcus species Streptococcus pyrogens

Methanol Shoot

Methanol

Fungi Ammer et al. [55] Dhiman et al. [56] Bora et al. [57] Modilal et al. Modilal et al. (2015) Farooqui et al. [58]

Pseudomonas species

Pseudomonas aeruginosa Klebsiella pneumonia Staphylococcus aureus Streptococcus pyogenes Bacillus subtilis Streptococcus pneumoniae Bacillus subtilis Micrococcus Staphylococcus aureus

Farooqui et al. [58]

Juglans regia

Walnut

Juglandaceae

Bark

Methanol

Psidium guajava

Amrood

Myrtaceae

Leaf

Ethanol

Jasminum officinale

Jasmine

Oleaceae

Leaf

Aequous

Mazus goodenifolius

Kuntze/floramaster Phrymaceae

Essential oil

Essential oil

Pasturella multocida Staphylococcus aureus

Datura stramonium

Dhatura

Leaf

Benzene extract

Micrococcus luteus

Klebsiella pneumoniae

Staphylococcus aureus

Enterobacter Pseudomonas aeruginosa

Cold maceration Cold maceration

Staphylococcus aureus

Pseudomonas pickettii

Bibi et al. [63]

Micrococcus luteus

Salmonella setubal

Bibi et al. [63]

Sarcina lutea Staphylococcus epidermidis Enterococcus faecalis Enterococcus faecalis

Klebsiella pneumoniae Serratia marcescens, Pseudomonas aeruginosa

Hajji et al. [64]

Klebsiella pneumoniae. Pseudomonas aeruginosa Escherichia coli Pseudomonas aeruginosa

Sharma et al. [65] Sharma et al. [65] Sharma et al. [65] Sharma et al. [65]

Solanaceae

Pistacia integerrima

Villanay

Anacardiaceae

Shoot

Toona ciliata

Mahanim

Meliaceae

Leaf

Tribulus terrestris Mirabilis jalapa L.

Markunday Gule sakbar

Zygophyllaceae Nyctaginaceae

Seeds Tubers

Ethanol Petroleum ether

Ocimum sanctum Terminalia chebula Zingiber officinale Cinnamomum cassia

Lamiaceae Combretaceae Zingiberaceae Lauraceae

Leaf Leaf Rhizome Bark

Methanol Methanol Ethanol Ethanol

Acacia nilotica

Tulsi Harad Adrak Sthula tvak, Taja kekar

Leguminosae

Root

Methanol

Caryophyllus aromaticus Cichorium intybus

lavang/qaranful Kashni

Myrtaceae Asteraceae

Flower buds Leaf

Methanol Aequous

Catharanthus roseus

Periwinkle

Apocynaceae

Pasteurella multocida.

Farooqui et al. [58]

Vibrio cholerae vibrio parahaemolyticus Escherichia coli Proteus vulgaris Pseudomonas aerogenosa

Farjana et al. [59]

Pseudomonas fluorescens Enterococcus sp.

Salmonella Typhimurium Agrobacterium radiobacter Erwinia carotovora Pseudomonas fluorescens Chromobacterium

Khan et al. [60] Rhizopus solani Aspergillus niger Aspergillus flavus Alternaria alternata Aspergillus niger

Riaz et al. [61]

Gul et al. [62]

Aspergillus fumigatus Saccharomyces cerevisiae

Aspergillus flavus, Fusarium verticillioides,

Mahesh and Satish [66] Ushimaru et al. [67] Petrovic et al. [68]

Enterobacter faecalis

Srinivasan et al. [69]

M. Bilal et al. / International Journal of Biological Macromolecules 103 (2017) 554–574

Eucalyptus tereticornis Centella asiatica Azadirachta indica Solanum nigrum

Reference Gram Negative

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Table 4 Some medicinal plants-derived antimicrobial compounds with their antimicrobial mechanism of action. Compounds name

Mechanism of action

Alkaloids

Intercalate into DNA double helix and uncouple respiration

Pandey and Kumar [73]

Carvacrol

Disruption of bacterial cell membrane

Holley and Patel [74]

Cinnamaldehyde

Diminishing the intracellular ATP by ATPase stimulation

Pandey and Kumar [73]

Coumarin

Effectiveness on genetic affairs

Pandey and Kumar [73]

Eugenol

Membrane disruption, inhibition of ATPase actuality and liberation of intracellular ATP

Burt [75]

Flavonoids

Metal chelating, Adhesion binding, cell wall complexation

Cowan [76]

Phenolics

Efficacy on membrane infraction

Cowan [76]

Phenols

Metal chelating

Cowan [76]

Quinones

Adhesin binding, complex with cell wall, enzyme inactivation

Pandey and Kumar [73]

Terpenoids

Membrane disruption, prohibition of ATPase actuality

Cowan [76]

Tannins

Adhesin binding, cell wall complexation, enzyme inactivation, membrane disruption, substrate deprivation

Pandey and Kumar [73]

Thymol

Membrane infraction, prohibition in deliverance of intracellular ATP and other constituents of microorganisms

Burt [75]

reliant pathway for metal-assisted oxidative stress is compelling [98,92,88,93,94]. In E. coli, endogenously accumulated compounds generating ROS led to damage DNA and resultantly inhibit the enzyme activities that are crucial to cell growth [99,80,81]. It is worth mentioning that different metals or their derivatives are distinctive in their chemistry with complex antimicrobial activity. It is, therefore, logical to assume that cellular growth inhibition and

Structure

References

death are the consequence of a concerted action of different mechanisms [77]. It is evident that these antimicrobial agents disrupt cell membrane, interfere with cell wall biosynthesis and cellular functions, interacts with cellular proteins and ligands, depolarizes membrane potential, and induces oxidative stress [82]. Performing in collaboration, these multiple mechanisms of action may

M. Bilal et al. / International Journal of Biological Macromolecules 103 (2017) 554–574

567

Fig. 1. Multiple mechanisms of antimicrobial action of nitric oxide-releasing nanoparticles (NO NPs), chitosan-containing nanoparticles (chitosan NPs), silver-containing nanoparticles (Ag NPs), zinc oxide-containing nanoparticles (ZnO NPs), copper-containing nanoparticles, titanium dioxide-containing nanoparticles (TiO2 NPs), and magnesium-containing nanoparticles (Reproduced from Pelgrift and Friedman [83]; with permission from Elsevier).

contribute to the compelling activity of metal-based antimicrobial agents against multidrug-resistant microorganisms. 3.2. Metal-based antimicrobial macromolecules In earlier studies, various essential, as well as non-essential metals, have been employed as antimicrobial moieties to develop metal-based antimicrobial macromolecules. This section appraises the macromolecules designed from the metals that provide the antimicrobial activity. 3.2.1. Copper The antimicrobial activity of copper is documented since ancient times, as it has long been utilized as a water disinfecting and food preserving agent. Xu et al. [100] developed a copper-based antimicrobial ultrafiltration polymeric membrane by integrating copper ions with the amino groups of polyethylenimine. The coordinated copper augments the antimicrobial activity of the membrane, and resultantly enhancing E. coli killing efficiency to 71.5% from 14.5% of the membrane lacking copper metal. A water-soluble copper-coordinated terpyridine carboxymethyl cellulose revealed important antibacterial and antifungal activities towards Gram-

positive, Gram-negative, and representative fungus. The designed polymer entirely impedes the evolution of the Gram-positive bacteria and the fungus as well as 90% of the Gram-negative bacteria [101].

3.2.2. Iron Iron is one of the transition metal that is an indispensable constituent of several metalloproteins, enzymes, electron-transfer systems, and oxygen storage and transport systems. Importantly, the iron redox chemistry catalyzes the generation of free radicals, which attack and damage cellular macromolecules, and causes tissue injury ultimately leading to cell death [102]. An initiative for the increasing interest in iron-based antimicrobial agents is the redox activated efficacy of the ferrocene derivative of chloroquine, ferroquine, against drug-resistant Plasmodium strains of malaria parasites [103,104]. Iron-based dendrons were accessed to be a new class of antimicrobial agents [105] potentially active against Grampositive S. aureus and Gram-negative E. coli. Recently Abd-El-Aziz et al. [106] developed a novel class of organo-iron antimicrobial dendrimers which showed antimicrobial property against a panel of Gram-positive methicillin-resistant S. aureus, vancomycin-

568

M. Bilal et al. / International Journal of Biological Macromolecules 103 (2017) 554–574

Fig. 2. A simplified death routes of NPs against a bacterial cell.

resistant E. faecium, and S. warneri; Gram-negative P. aeruginosa and Proteus vulgaris; and fungus C. albicans [106].

bactericidal activity was recorded against the tested microorganisms [109,110].

3.2.3. Platinum Platinum is the first transition metal to be incorporated into an authorized anticancer drug (cisplatin) due to its distinctiveness in the field of medicinal chemistry. Motivated by this development, the organometallic chemists encouraged to combat microbial infections with platinum-coordinated metallic compounds. Keeping this in view, the Carraher group fabricated various platinum-based polymers and tested their capability to inhibit E. coli growth and to affect viral replication [107]. The platinum-incorporated antiviral polymers considerably inhibit the growth of Reovirus ST3, Vaccinia WR, HSV-1, and VZV [108].

3.2.5. Silver Like copper, silver (Ag) is also acknowledged as an antimicrobial agent since antiquity that corroborated its application in the development of antimicrobial polymers with novel antimicrobial characteristics. Insoluble silver-coordinated polyoxometalates polymers designed by Lu et al. [111] were investigated to be excellent solid-state antimicrobial agents together with potential photocatalyst for the remediation of wastewater. The above-mentioned silver-incorporated polymers displayed broad spectrum potentiality in effectively suppressing the growth of Gram-positive and Gram-negative bacterial strains. Mechanistically, the silver-based polymers alter the concentration profile of the surrounding bacterial cells, disturbing ion balance, and leading to leakage of cytoplasmic materials, ultimately killing the microorganism [77].

3.2.4. Ruthenium Organometallic chemists continue to explore the potential of applying transition metals as antimicrobial agents. Ruthenium is an attractive metal because of its distinct biochemical properties that include its capability to bind proteins, enzymes, and DNA, altering their structure and plausibly stimulating cell viability. These properties of Ruthenium advocate the possibility to target bacterial proteins and enzymes, and eventually impeding the microorganism growth. With an aim to broaden the scope of ruthenium-based antimicrobial agents, Collins and coworkers designed inert di, tri, and tetranuclear polypyridylruthenium (II) complexes and appraised their activity towards several Grampositive as well as Gram-negative microbial isolates. A significant

4. Nanotechnology-based antimicrobials 4.1. Nanoparticles against drug-resistant bacteria The emergence of multidrug-resistant bacteria is recognized as a crucial challenge for public health. Fighting against antibioticresistant bacteria entails multiple expensive drugs with plausible adverse effects, and as a consequence, treatments are usually unaffordable and require more time. Nanoparticles can offer a novel

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strategy to challenge multidrug-resistant bacteria [112]. NPs have reported to shown toxic effects against P. aeruginosa, Burkholderia cepacia, methicillin-resistant S. aureus, multidrug-resistant Acinetobacter baumannii, and Klebsiella pneumoniae [112]. Targeting bactericidal NPs to specific infected tissue or specific bacteria is an efficient approach to controlling infection since this strategy curtails side effects and eventually augments antibacterial activity [113]. Fig. 2 illustrates a simplified death route of NPs against a bacterial cell. More importantly, multifunctional NPs could be very useful; e.g., multifunctional IgG–Fe3 O4 -TiO2 magnetic NPs exhibit important antibacterial activity and can target several pathogenic bacteria particularly Streptococcus pyogenes under UV irradiation [114]. These NPs displayed capability to disorganize and damage the cell membrane and increase the permeability, which ultimately leads to cell death. The polyvinyl alcohol (PVA)-coated ZnO NPs can internalize the bacteria and induce oxidative stress. The toxicity of ZnO NPs is concentration-dependent, and these NPs are mildly toxic at low concentration [115]. Amongst various metalincorporated NPs such as CuO, NiO, ZnO, and Sb2 O3 investigated against E. coli, B. subtilis, and S. aureus, the CuO-based NPs exhibited the highest toxicity, followed by ZnO, NiO and Sb2 O3 NPs [116]. CuO nanoparticles in elevated concentration were found to be effective in destroying a broad range of microbial pathogens involved in hospital-acquired infections [117]. The reduced amount of negatively charged peptidoglycans makes Gram-negative bacteria less prone to such positively charged antimicrobials. Noticeably, a high antimicrobial activity of copper nanoparticles was recorded against B. subtilis that might be ascribed to a greater abundance of amines and carboxyl groups on the cell surface of B. subtilis and increased affinity of copper towards these groups [118]. Toxicologically, these NPs can locally alter microenvironments around the bacteria and generate ROS, which in turn led to bacterial destruction [119]. Biogenic silver NPs acting synergistically with several antibiotics (such as erythromycin, chloramphenicol, ampicillin, and kanamycin) have profound antibacterial activity against Gram-positive and Gram-negative bacteria [120]. The antibiotics facilitate the internalization of silver NPs into the bacteria following damaging the cell wall. Once the NPs internalized, they bind to DNA and prevent DNA unwinding, resultantly leading to cell death. The titanium-modified silver NPs inhibit E. coli and S. aureus growth by naturally disrupting the membrane integrity [121]. The studies above suggest the suitability of silver NPs to combat against particular bacteria. Although, the exact mechanisms of action of NPs toxicity against various bacterial strains are not explored completely; it is hypothesized that antimicrobial nanoparticles tackle multiple biological pathways found in broad species of microbes (Fig. 3). The NPs have a tendency to attach to the bacterial membranes by electrostatic interaction and disorganize the integrity of the bacterial membrane [123]. Nano-assisted toxicity is elicited through inducing oxidative stress by free radical generation following the introduction of NPs [124]. Numerous studies have reported the antibacterial properties of various NPs, but some reports remain controversial with each other [125–128]. All these reports in general, indicate that the mechanisms of NPs toxicity are very complicated depending on several physicochemical properties of NPs. 4.2. Metallic nanoparticles Metallic NPs are usually synthesized by chemical reduction of any metallic salt (aluminum/gold/silver/silica or titanium) with a reducing agent and, their unique chemo-physical, optical and biological characteristics can be manipulated depending on the desired applications [129]. They can also be synthesized by “green” methods, using biological agents such as bacteria, actinomycetes,

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Fig. 3. Various antimicrobial mechanisms of nanomaterials (Reproduced from Huh and Kwon [122]; with permission from Elsevier).

yeast, fungi or algae [130,131]. These “green” methods are cleaner and eco-friendlier than chemical ones. They suffer from the problem of the extraction and purification of NPs because unwanted residue may produce adverse reactions [130,131]. The nanoparticles are broadly congregated into organic and inorganic (metallic) nanoparticles. Inarguably, the metallic nanoparticles have gained vital importance due to their ability to withstand adverse processing conditions [132]. The metallic nanoparticles are thoroughly being explored and extensively investigated as potential antimicrobials. Compared with organic NPs (liposomes, polymeric NPs, polymeric micelles and solid lipid NPs (SLNs), metallic NPs can be smaller (a size range between 1 and 100 nm), and their loading efficacy is much higher [133] and they possess potential antimicrobial properties; for example, Silver nanoparticles have well-known antimicrobial properties, ad also support the efficacy of antimicrobial treatments when they are exploited as carriers, indicating their main therapeutic application the antimicrobial field [134]. Recently, Cavassin and co-workers (2015) have comparatively evaluated different methods to detect the in vitro activity of silver nanoparticles (AgNP) against multidrug resistant bacteria. According to them, the most significant decrease in the colony forming units (CFU) within the lesser period occur using chitosan AgNPs against the MSSA isolate (4 dilutions) and MRSA isolates. After 12 h the MDR microorganism decreased its multiplication reaching the initial number of CFU, while the multiplication of antimicrobial-susceptible isolates remained until the end of 24 h, the low counts were reached after the 6th hour (Fig. 4). Among Gram-negative, the greatest reduction was observed for chitosan AgNPs against MDR-K. pneumoniae and antimicrobial susceptible isolate of E. aerogenes (Fig. 5) [135]. More importantly, these NPs are also useful for the development of medical devices with a viewpoint to preventing infectious diseases. Recently, it has been reviewed that they have been employed in trauma and dental implants, prostheses and bone cement [136]. Silver ions released by active surfaces of silver nanoparticles are described to be the tangible biocidal agents [113]. These silver ions penetrate into the bacterial cells, where they are reduced as the cell endeavors to eliminate them from the cell interior, that ultimately leading to cell destruction. It has also been revealed that silver nanoparticles of smaller particle sizes create pores on the bacterial cell walls, and as a result, the cytoplasmic contents are discharged to the medium, which leads to cell death [137]. In recent years, a large number of studies have evaluated the antimicrobial activities of the silver nanoparticles against a panel of pathogenic. Overall,

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Fig. 4. Comparison of time-kill curves for one oxacillin-resistant S. aureus (MRSA) and one oxacillin-suscpetible S. aureus (MSSA) isolate, using AgNPs particles (citrate, chitosan and PVA) and controls (silver sulfadiazine, silver nitrate and commercial AgNPs). For MRSA was made the comparison using MHB II broth and MHB II blood 1.25%. MHB II- Mueller–Hinton Broth cation adjusted and microorganism; MHB II CTL-control without microorganisms. MHB II SGE-microorganism and broth enriched with blood; MHB II CTL SGE-only broth and blood. For oxacilin-susceptible S. aureus (MSSA3), silver sulfadiazine and silver nitrate curves were not done due to high MICs (Ag Sulfad and Ag Nitrate: MIC ≥27 ␮g mL−1 ; MBC ≥27 ␮g mL−1 ) (Reproduced from Cavassin et al. [135]; an open access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)).

the maximum antimicrobial activity experimented against S. aureus followed S. epidermidis and S. pyogenes. In the case of gram-negative pathogens such as Salmonella typhi and Klebsiella pneumonia, a moderate activity was recorded microorganisms [138–142]. ZnO NP could potentially be used as a suitable antibacterial agent against foodborne pathogens, especially Bacillus subtilis, E. coli and Pseudomonas fluorescens [143]. There are also some reports confirming the potent antimicrobial activity of ZnO nanoparticles wherein these nanoparticles completely lyse the food-borne bacteria Salmonella typhimurium and Staphylococcus aureus [144]. In another study, ZnO nanoparticles (12 nm) inhibited the growth

of E. coli by disintegrating the cell membrane and increasing the membrane permeability [145] suggesting growth inhibiting the potential of ZnO nanoparticles against pathogenic bacteria. At very high concentrations, alumina nanoparticle can exhibit a mild growth-inhibitory effect. This growth-inhibiting effect is attributed to surface charge interactions among the alumina particles and bacterial cells. Possibly, it can be assumed that the free-radical scavenging properties of the alumina particles might have prevented cell wall disruption and drastic antimicrobial action [146]. Other metallic NPs developed from aluminum, copper, iron, palladium, platinum, zinc or titanium also possess antimicrobial

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Fig. 5. Comparison of time-kill curves for a carbapenem-resistant K. pneumoniae (KPC) isolate and an isolate of carbapenem-susceptible E. aerogenes, using AgNPs particles (citrate, chitosan and PVA) and controls (silver sulfadiazine and silver nitrate). MHB II- Mueller Hinton Broth cation adjusted and microorganism; MHB II CTL- control without microorganisms. For commercial AgNPs control the curve was not done due to high MICs (MIC ≥ 10 ␮g mL−1 ; MBC ≥ 10 ␮g mL−1 ) (Reproduced from Cavassin et al. [135]; an open access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)).

activities and have been used as carriers to improve the therapeutic effect of different antimicrobial agents. An original study reported the TiO2 NPs antibacterial efficiency in the order of E. coli > P. aeruginosa > S. aureus > E. faecium > C. albicans, is seemingly determined by the complexity and the density of the cell membrane/wall depending on the thickness of microbial surface structure [147]. Growth inhibition of Enterobacter cloacae by UVA-irradiated TiO2 NPs was less effective than that of E. coli and P. aeruginosa [148]. 5. Concluding remarks and future perspectives For more than a half-century, antibiotics have been saving a massive number of lives from many infectious diseases. Nevertheless, the emergence of antibiotics resistance by microbial variants is a serious threat in fighting against infectious diseases. It becomes clear that overcoming antibiotic resistance by devel-

oping more powerful antibiotics, which has been attempted by pharmaceutical companies, can lead to an only limited and temporary success and eventually contribute to developing greater resistance. There is a dire need to discover some new plant-derived natural compounds as antimicrobial agents with diverse chemical structures and novel mechanisms of action. Scientists from different research backgrounds have found thousands of phytochemicals with their antimicrobial usefulness on all types of microorganisms in vitro. An enormous variety of secondary metabolites, such as alkaloids, flavonoids, tannins, and terpenoids, with profound antimicrobial potentialities, have considerably drawn the interest of ethnopharmacologists, botanists, microbiologists and natural product chemists towards plant utilization as efficient, safe and natural products. The biggest challenges include finding compounds with sufficiently lower minimum inhibitory concentrations (MICs), little toxicity, and ease bioavailability for efficient and safe use in

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humans and animals. In recent years, the new approaches targeting specific regulatory pathways and bacterial virulence are becoming the paradigm of antibacterial-based therapeutics. The mechanisms of action of these compounds would certainly pave the path for the designing and development of novel drugs that could potentially control infectious diseases together with circumventing antimicrobial resistance. The above-discussed data shows the potential of metal nanoparticles (MNPs) as potent antimicrobial bullets with proven advantages. The green biosynthesis of NPs has following major advantages among others i.e. (1) natural plants which are renewable and eco-friendlier, (2) NPs synthesis process is easy to scale up, (3) overall cost-effective ratio is net positive, (4) carbon neutral, (5) stable formulations with adjustable sizes and shapes, (6) no or less consumption of harsh chemicals, and (7) no or less toxic contaminants/by-products, etc. There is a dire need to engineer multifunctional NPs on a pilot scale. Many researchers have directed or redirecting their interest to explore new dimensions in biotechnology at large and nanotechnology in particular. In summary, the present review work aimed at combatting AMR, and research that underpins the development of strategies to mitigate the effects e.g. through novel alternatives to antimicrobials. A large variety of various NPs has been scrutinized as efficient antibiotics delivery vehicles which also protect antimicrobial drugs from a resistant mechanism in a target microbe. Most prominently, NPs permit relating multiple independent and potentially synergistic approaches on the same platform to boost antimicrobial activity and overcome resistance to antibiotics. Through judicious design, multifunctional characteristics of NPs can be modified to achieve optimal infective capability and therefore enhanced antibacterial control. Of many different approaches investigated to respond antimicrobial resistance, metal-based antimicrobials and utilization of nanoparticles as antibiotics carriers appears to hold great promise. Conflict of interest We do not have any conflicting, competing and financial interests in any capacity. Acknowledgements The authors are grateful to the Shanghai Jiao Tong University, Shanghai200240, China, and Tecnologico de Monterrey, Mexico for providing literature facilities. References [1] I. Roca, M. Akova, F. Baquero, J. Carlet, M. Cavaleri, S. Coenen, G. Kahlmeter, The global threat of antimicrobial resistance: science for intervention, New Microbes New Infect. 6 (2015) 22–29. [2] G.H. Talbot, J. Bradley, J.E. Edwards, D. Gilbert, M. Scheld, J.G. Bartlett, Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America, Clin. Infect. Dis. 42 (5) (2006) 657–668. [3] H.W. Boucher, G.H. Talbot, J.S. Bradley, J.E. Edwards, D. Gilbert, L.B. Rice, J. Bartlett, Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America, Clin. Infect. Dis. 48 (1) (2009) 1–12. [4] B. Tepe, D. Daferera, M. Sökmen, M. Polissiou, A. Sökmen, In vitro antimicrobial and antioxidant activities of the essential oils and various extracts of Thymus eigii M. Zohary et pH Davis, J. Agric. Food Chem. 52 (5) (2004) 1132–1137. [5] H.O. Edeoga, D.E. Okwu, B.O. Mbaebie, Phytochemical constituents of some Nigerian medicinal plants, Afr. J. Biotechnol. 4 (7) (2005) 685–688. [6] H. Edeoga, D. Okwu, B. Mbaebie, Phytochemical constituents of some Nigerian medicinal plants, Afr. J. Biotechnol. 4 (7) (2005) 685–688. [7] K. Dhama, R. Tiwari, S. Chakraborty, M. Saminathan, A. Kumar, K. Karthik, A. Rahal, Evidence based antibacterial potentials of medicinal plants and herbs countering bacterial pathogens especially in the era of emerging drug resistance: an integrated update, Int. J. Pharmacol. 10 (2014) 1–43.

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