Interplay of antibiotic resistance and food-associated stress tolerance in foodborne pathogens

Journal Pre-proof Interplay of antibiotic resistance and food-associated stress tolerance in foodborne pathogens Xinyu Liao, Yanna Ma, Eric Banan-Mwine Daliri, Shigenobu Koseki, Shuai Wei, Donghong Liu, Xingqian Ye, Shiguo Chen, Tian Ding PII:

S0924-2244(19)30565-5

DOI:

https://doi.org/10.1016/j.tifs.2019.11.006

Reference:

TIFS 2655

To appear in:

Trends in Food Science & Technology

Received Date: 25 July 2019 Revised Date:

11 November 2019

Accepted Date: 12 November 2019

Please cite this article as: Liao, X., Ma, Y., Banan-Mwine Daliri, E., Koseki, S., Wei, S., Liu, D., Ye, X., Chen, S., Ding, T., Interplay of antibiotic resistance and food-associated stress tolerance in foodborne pathogens, Trends in Food Science & Technology (2019), doi: https://doi.org/10.1016/j.tifs.2019.11.006. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

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Interplay of Antibiotic Resistance and Food-associated Stress

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Tolerance in Foodborne Pathogens

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Xinyu Liaoa,b, Yanna Maa,b, Eric Banan-Mwine Daliric, Shigenobu Kosekid, Shuai

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Weic, Donghong Liua,b,, Xingqian Yea,b, Shiguo Chena,b, Tian Dinga,b*

a

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Department of Food Science and Nutrition, National Engineering Laboratory of

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Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou,

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Zhejiang 310058, China;

b

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Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture,

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Zhejiang Key Laboratory for Agro-Food Processing, Hangzhou, Zhejiang 310058,

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China

c

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Department of Food Science and Biotechnology, Kangwon National University,

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Chuncheon, 200-701, South Korea

d

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Food Processing Laboratory, National Food Research Institute, 2-1-12, Kannondai,

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Tsukuba, Ibaraki 305-8642, Japan

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*Corresponding author.

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E-mail address: [email protected]

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Abstract

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Background

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The discovery and use of antibiotics have produced tremendous benefits for human

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society, however, with the large-scale use of antibiotics in medicine, animal

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husbandry and other fields, more and more antibiotic-resistant bacteria have emerged.

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Since diseases caused by such antibiotic resistant bacteria could require more drastic

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measures to treat, the emergence of such resistant bacteria in food has attracted much

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concern.

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Scope and Approach

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In this review, we summarized the interplay between antibiotic resistance and

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food-associated stress tolerance, and the hypothesized molecular mechanisms for the

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cross protection in bacteria.

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Key Findings and Conclusions

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In this review, we found that some common food-associated stresses, such as cold,

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acid, osmosis and sanitizers could provide cross protection for bacteria against

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antibiotics. In turn, antibiotic resistance could also render bacteria more tolerant to

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food-associated stresses. Meanwhile, novel nonthermal technologies may more likely

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result in little or no difference in bacterial antibiotic resistance, and this can be an

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advantage over traditional sterilization methods. Several molecular mechanisms for

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the cross protection between antibiotics and food-associated stresses have been 2

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discussed in this review. General stress response (e.g., sigma factors and

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two-component system), SOS response, mutations, and other mechanisms have been

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proposed as strategies for bacteria acquisition of cross protection.

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Keywords: Antibiotic-resistant bacteria; food-associated stresses; mechanisms;

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cross-protection; food safety.

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1. Introduction Infections caused by antibiotic-resistant bacteria are increasing in recent years,

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and this has become a major public health problem (Caniça, Manageiro, Abriouel,

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Moran-Gilad, & Franz, 2019; Economou & Gousia, 2015). This problem puts

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tremendous pressure on medical systems and leads to high cost treatment and low

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cure rates (Levy & Marshall, 2004). According to a report by O’Neill (2018), over

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700,000 deaths are recorded per year from antibiotic-resistant strain infections, and

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this number will increase to 10 million by 2050. This means countries would have to

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pay trillions of dollars to treat such infections (O’Neill, 2018). In view of this, “Food

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safety” was selected as the theme for 2015 World Health Day, and antimicrobial

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resistance was considered as a major threat. Governments and stakeholders were

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called upon to implement policies and practices that prevent the emergence of

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multidrug-resistant bacteria (WHO, 2014).

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The use of antibiotics to treat diseases and promote crop growth in agriculture

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results in the emergence of antibiotic-resistant bacteria and the enhancement of

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bacterial resistance in the intestine, animal excreta and the surrounding environment

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(Aarestrup, 2010; Oniciuc, et al., 2018). Antibiotic-resistant bacteria, especially

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zoonotic bacteria which infect edible animals can be transmitted to humans via the

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food chain or skin contact (Soonthornchaikul & Garelick, 2009). Since many studies

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have shown that antibiotic-resistant genes can be transferred in the human

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gastrointestinal tract, consuming food containing antibiotic-resistant bacteria may

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promote the transfer of resistant genes to human pathogens in the gut (Fig. 1) (Hwang,

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Kim, & Kim, 2017). Therefore, antibiotic-resistant bacteria could accumulate and

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transform humans into an “antibiotic-resistance gene bank”, posing a great threat to

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human (Cabello, 2010).

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From farm to fork, foods need to be processed through various techniques such

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as frying, heating, marinating, and baking. Thus, bacteria might encounter with

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various physical and chemical stresses (e.g., acids, oxidants, osmosis, heating,

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freezing) during food processing and storage (Wesche, Gurtler, Marks, & Ryser, 2009)

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(Table 1). Using these methods for processing can efficiently inactivate pathogens,

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extend the shelf life of foods, hence ensuring food safety to a certain extent. However,

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such food-associated stresses may trigger adaptation responses in bacteria due to

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numerous genetic and physiological adjustments which would eventually render the

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bacteria significantly resistant to other stresses. Furthermore, bacteria adaptive

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response to various food-associated stresses have been shown to confer cross

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protection to antibiotics, which may accelerate the dissemination of antibiotic

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resistance in the food chain (Huang, Hu, Wu, Wei, & Lu, 2013; Zhang, Xu, Wang,

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Zhuang, & Liu, 2017).

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The purpose of this review is to summarize the interplay of antibiotic resistance

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and stress tolerance to heat, cold, acid, osmolarity and emerging nonthermal

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technologies used in food production. In addition, the molecular mechanisms for the

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cross-protection between antibiotics and other stresses were discussed in detail.

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2. The interplay of antibiotic resistance and food-associated stress tolerance In this part, the role of antibiotic resistance in the tolerance of bacteria to food

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-associated stresses (Table 2) and the effect of preexposure to food-associated stimuli

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on the antibiotic resistance profiles (Table 3) are discussed below.

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2.1. Heat and antibiotic resistance

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Thermal pasteurization is a conventional sterilization method widely used in

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food industry (Li & Farid, 2016). Extreme heat poses adverse damage on the quality

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attributes of food. Thus, mild heat (45-60℃) is preferable in food industry (Lado &

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Yousef, 2002). However, inefficient inactivation of microorganisms by mild heat

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tends to trigger bacterial stress response. The effect of antibiotic resistance on thermal

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tolerance of bacteria has been reported in many studies. In a study of Walsh, et al. 5

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(2010), the D-values for wild type Listeria monocytogenes strains (NCTC 11994 and

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NCTC 12480) did not differ from those obtained for their streptomycin-resistant

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mutants (M63 and M102) when exposed to 55℃. Komora, Bruschi, Rui, Ferreira, &

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Teixeira (2017) found no significant differences for the tolerance of antibiotic

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susceptible and antibiotic resistant L. monocytogenes to thermal pressure (58℃, 60

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min).

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et al. (2010) showed that wild type Yersinia enterocolitica possessed higher resistance

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to 50-60℃ than their nalidixic acid resistant counterparts did. Dombroski, Jaykus,

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Green, & Farkas (1999) reported that the D-values at 47℃ was much lower for wild

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type Vibrio vulnificus than their nalidixic acid resistant mutants. Duffy, Walsh, Blair,

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& Mcdowell (2006) observed a much lower D value at 55℃for multi-antibiotic

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resistant (MAR) Escherichia coli O157:H7 than their resistant susceptible strains,

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indicating the susceptibility of MAR E. coli O157:H7 to thermal stress. This

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resistance weakening might be attributed to an overall “cost” induced by antibiotic

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resistance, which weakened their competitiveness compared with antibiotic

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susceptible strains (Morse, O'Hanlon, Virji, & Collins, 1999). Vice versa, the role of

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thermal adaptation has also identified to the bacterial antibiotic resistance. Ebinesh,

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Vijaykumar, & Kiran (2018) reported that the exposure to a suboptimal temperature

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of 45℃ rendered the resistance of Acinetobacter baumannii to amikacin, norfloxacin,

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piperacillin, tazobactam, imipenem, meropenem. In another study of Mcmahon, Jiru,

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Moore, Blair, & Mcdowell (2007), resistance of E. coli to amikacin, ceftriaxone,

Antibiotic resistance was even shown to impair the thermal tolerance. Doherty,

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nalidixic acid, the resistance Salmonella enterica serovar Typhimurium to Amikacin,

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ceftriaxone, trimethoprim and resistance of Staphylococcus aureus to amikacin,

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ceftriaxone, trimethoprim was decreased after thermal treatment of 45℃. However,

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once the thermal stressor was removed, the increased susceptible would not be

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retained in E. coli, Salmonella enterica and S. aureus. Such temporary changes in

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antibiotic sensitivity might be caused from the compromise in membrane fluidity,

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which inhibited antibiotic extrusion.

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2.2. Cold and antibiotic resistance

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Bacteria encounter low temperature stress when freezing food for the

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preservation. Cold has been indicated to be related to the alteration in antibiotic

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resistance profile of bacteria. Cold (5℃, 24 h) stressed Cronobacter sakazakii was

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observed to have smaller zoom of inhibition (ZOI) to amikacin, norfloxacin,

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piperacillin, tazobactam, imipenem, meropenem than unstressed counterparts (Anas A

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Al-Nabulsi, et al., 2011). Similarly, Al-Nabulsi, et al. (2015) reported that the cold

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exposure (10℃, 24h) could enhance the resistance of L. monocytogenes towards

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streptomycin, enrofloxacin, gentamycin, penicillin, tetracycline, ciprofloxacin,

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doxycycline, vancomycin, and ampicillin. More interestingly, the authors found that

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even after removing cold stress, the tolerance of L. monocytogenes to antibiotics did

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not vanish.

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2.3. Osmosis and antibiotic resistance 7

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Salt (e.g., NaCl) can disrupt osmotic balance between the intracellular and

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cytoplasmic environments to pose osmotic pressure on bacterial cells (Burgess, et al.,

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2016). Such inhibitory effects make salt as a common preservative in various food,

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including fermented foods, seafood, and ready-to-eat (RTE) meat, such as baked

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goods, fruit and vegetables, salami, cheese (Desmond, 2006). In addition, when food

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is digested, bile salt in human intestine also provide a hyperosmotic environment for

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bacteria contained in food. The relationship between osmotic stress and antibiotic

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resistance has been reported in some studies. Komora, et al. (2017) observed that the

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antibiotic resistance could confer higher tolerance of L. monocytogenes toward

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osmotic stress (37% NaCl, 7 d). In addition, multi-antibiotic resistant L.

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monocytogene showed higher osmotic resistance than the strains with resistance to

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one antibiotic did. Similar results were obtained in a study of Ma, et al. (2019), who

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found that the antibiotic resistant S. aureus possessed higher capacity to survive under

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osmotic condition (30% NaCl, 9 days) than antibiotic susceptible ones did. In turn,

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osmotic pressure was also found to affect the antibiotic resistance profile of bacteria.

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Al-Nabulsi, et al. (2015) reported that after exposing to NaCl (2, 4, 6,12%) for 24 h, L.

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monocytogenes became less susceptible to ampicillin, tetracycline, doxycycline and

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vancomycin. Similarly, Zhu & Dai (2018) also noticed that the high salt condition

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(0.4 M NaCl) provided a cross-protection for E. coli against tetracycline and

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chloramphenicol.

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2.4. Acid and antibiotic resistance 8

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Bacteria often encounter low pH condition either in food with acidic additives

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(e.g., organic acids) or within human stomach or macrophage phagosome vacuole

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(Begley & Hill, 2015). Numerous publications have studied the interplay of antibiotic

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resistance and acid tolerance of bacteria, and different conclusions were acquired in

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different studies. In a study of Komora, et al. (2017), the inactivation levels of

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antibiotic susceptible L. monocytogenes were found to be much higher than those of

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antibiotic resistant strains under acidic condition (1% lactic acid, 60 min). Ma, et al.

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(2019) also demonstrated that antibiotic resistant S. aureus showed lower mortality to

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strong acid exposure (HCl, pH = 1.5, 40 min) compared with antibiotic susceptible

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counterparts. Mitosch, Rieckh, & Bollenbach (2017) found that pretreatment of

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trimethoprim gave cross protection for E. coli to stand against subsequent acid stress

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(HCl, pH=3). However, opposite results were obtained by other studies. In a study of

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Duffy, et al. (2006), who reported that it was easier for antibiotic resistant E. coli

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O157:H7 to be inactivated in yogurt and low pH juices than antibiotic susceptible E.

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coli O157:H7 did. Al-Nabulsi, et al. (2011) found comparative ability was observed

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between antibiotic resistant and antibiotic susceptible Salmonella when exposed to

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three kinds of acidic treatments, including acetic acid (2%), lactic acid (2%), and

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FreshFX (pH 1.5). Hughes, et al. (2010) also indicated that lactic acid (3%) and

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acidified sodium chloride (100 ppm) resulted in no difference of the inactivation level

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for antibiotic resistant and susceptible Salmonella. Such bare effect of antibiotic

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resistance on acid tolerance was also observed in the study of Cunha, et al. (2016).

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Regarding the impact of acid stress on antibiotic resistance, Al-Nabulsi, et al. (2015)

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found that dairy and meat isolated L. monocytogenes with preadaptation in acid

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environment (lactic acid, pH 5.5 to 6.0, 30 min) possessed higher resistance to

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antibiotics compared with unstressed strains. De Sales, et al. (2018) reported that

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simulated esophagus-stomach conditions (pH 2.0 – 3.8) assisted Salmonella to

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develop the resistance to the following antibiotics. Ebinesh, et al. (2018) also

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observed acid-stressed A. baumannii increased their resistant capacity to amikacin,

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norfloxacin, piperacillin+tazobactam, imipenem, and Meropenem. Al-Nabulsi, et al.

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(2011) observed that C. sakazakii cells with acid adaptation (pH 3.5, 30 min) showed

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more susceptible to streptomycin, gentamicin, kanamycin and doxycycline, most of

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which were aminoglycosides, but more resistant to tetracycline, tilmicosin, florfenicol,

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amoxicillin, ampicillin, vancomycin and neomycin, ciprofloxacin, and enrofloxacin,

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which mainly belonged to penicillin and fluoroquinolones. It seems that the

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cross-protection effect of acid stress against antibiotics depends the type of antibiotics

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used.

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2.5. Sanitizers and antibiotic resistance

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Sanitizers (e.g., benzalkonium chloride) are commonly used for the

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decontamination of food or food processing equipment. The relationship between

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antibiotic resistance and sanitizers has been reported in some studies. Fouladkhah,

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Geornaras, & Sofos (2013) observed no changes in the tolerance of susceptible and

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multidrug resistant Salmonella on quaternary ammonium compound-based (QAC), 10

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and acid-based (AB) sanitizers. Regarding the effect of sanitizers on antibiotic

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resistance profiles, Yu, et al. (2018) reported that the exposure of L. monocytogenes to

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benzalkonium chloride-a common sanitizer increased the resistance to cefotaxime,

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cephalothin and ciprofloxacin. The results from the work of Randall, et al. (2007)

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indicated that preexposure of Salmonella to an aldehyde-based disinfectant (ABD)

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increased MIC of ciprofloxacin by 2 folds, and pretreatment of a phenolic farm

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disinfectant (PFD) resulted in 2-fold increase in MIC of chloramphenicol. Potenski,

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Gandhi, & Matthews (2010) found that the preexposure of Salmonella to chlorine,

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sodium nitrite and sodium benzoate enhanced the resistance to tetracycline,

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chloramphenicol, nalidixic acid, and ciprofloxacin.

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2.6. Nonthermal technologies and antibiotic resistance

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The demand of consumers for freshness and nutrition has induced the

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development of various nonthermal sterilization technologies in order to assure food

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safety and retain the food quality (Barba, Koubaa, do Prado-Silva, Orlien, & de Souza

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Sant’Ana, 2017). Nonthermal technologies, including ultrasound, high pressure, pulse

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electric filed, irradiation, ultraviolet light, nonthermal plasma, allow to inactivate

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foodborne pathogens at a relatively low temperature and pose a mild effect on food

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products. However, the knowledge of nonthermal treatment on the physiological

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behaviors of microorganisms is still limited, which hinders the safe application of

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nonthermal technologies in food industry. The interplay of antibiotic resistance and

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tolerances towards nonthermal treatments has been noticed in recent years. Templeton, 11

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Oddy, Leung, & Rogers (2009) found that the tolerance of ampicillin and

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trimethoprim-resistant E. coli to UV exposure did not increased compared with the

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antibiotic susceptible ones. However, Zhang, et al. (2017) reported that higher UV

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dose (20 mJ/cm2) was required for antibiotic-resistant E. coli to achieve the

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comparable inactivation level to antibiotic susceptible strains, which can be achieved

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with UV dose of 8 mJ/cm2. Skowron, et al. (2018) found that the doses of gamma

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irradiation and electron beam for multidrug-resistant L. monocytogenes was much

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higher than those for drug-susceptible counterparts. Mortazavi, et al (2015) observed

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that ultrasound exposure made sensitive Klebsiella pneumonia resistant to cephalexin,

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however, ultrasound cannot change the antibiotic resistance profile of S. epidermidis,

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S. aureus and Salmonella. Guo, et al. (2018) reported that the atmospheric nonthermal

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plasma and plasma-activated saline exposure increased the sensitivity of S. aureus to

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tetracycline, rifampicin, gentamycin, vancomycin, chloramphenicol, ciprofloxacin,

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and clindamycin. Taheri, et al. (2015) have shown that preexposure to 2.4 GHz

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electromagnetic radiofrequency radiation significantly increased the antibiotic

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sensitivity of K. pneumoniae. The permeability enhanced by radiation assisted the

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entrance of antibiotics, which led to high accumulation of antibiotic and enhanced

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antibiotic sensitivity. Segatore, et al. (2012) found that the electromagnetic field

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pretreatment increased the susceptibility of E. coli and Pseudomonas aeruginosa

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toward kanamycin through modification of cell membrane charge distribution for

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better binding with kanamycin. Kanamycin, as an aminoglycoside antibiotic, carry

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positive charges, which can reversibly bind to anionic components in cell membrane

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to lead to bacterial death. Most above mentioned nonthermal treatment are more

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likely to decrease the antibiotic resistance, which mostly might be attributed to

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multitarget-mediated inactivation mechanisms, involving cell walls and membranes,

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intracellular components (Manas & Pagan, 2005). Cumulative damages on bacteria

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result in the irreversible bactericidal effect. Still, more investigations are required to

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test the relationship between antibiotic resistance and emerging nonthermal

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technologies.

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3. Molecular mechanisms for cross-protection between antibiotic resistance and

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food-associated stress tolerance Cross susceptibility among antibiotic resistance and food-associated stress

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tolerance is preferable to increase the inactivation level, however, cross protection

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will pose huge potential risk to food safety and human health. Thus, the molecular

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mechanisms underlying cross protection between antibiotic resistance and other stress

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tolerance require better understanding for controlling the spread of antibiotic

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resistance and assuring food safety.

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3.1. Sigma factors

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Sigma factors are the well-known general regulators of bacteria in response to

264

diverse stresses, including heat, cold, acid, osmolarity, oxidative stress, and so on

265

(Cebrián, et al., 2010). The sigma factors in Gram-positive bacteria and

13

S

(RpoS) and σB (SigB), respectively (Boor, 2006). Both

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Gram-negative are called

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RpoS and SigB belong to the σ70 family sigma factors, which are mainly related to

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bacterial stress response. The role of sigma factors is to bind to RNA polymerase

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(RNAP) core enzymes, which is then directed to the promoter of DNA sequence for

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transcription initiation (Fig. 2a) (Browning & Busby, 2016). Some studies also

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confirmed the regulatory effect of sigma factors under antibiotic exposure (Julia

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Elisabeth, Heike, & Michael, 2002; Qingchun, et al., 2012). Schulthess, et al. (2009)

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found that S. aureus with deletion in σB showed lower resistance to methicillin,

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teicoplanin and vancomycin. Thus, the shared sigma factor-dependent regulation

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mechanisms can lead to cross protection between antibiotics and food-associated

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stresses. Kindrachuk, Lucía, Manjeet, & Hancock (2011) discovered that the sigma

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factor RpoH involved in both heat tolerance and aminoglycoside resistance in P.

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aeruginosa. The heat shock (42℃) resulted in the overexpression of sigma factor

279

RpoH, which subsequently led to the overexpression of the asrA gene. The gene asrA

280

is responsible for encoding the aminoglycoside-induced stress response

281

ATP-dependent protease, which renders the resistance to aminoglycoside. In addition,

282

Mitosch, et al. (2017) found that the pretreatment of trimethoprim resulted in the

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depletion of adenine nucleotides, which further caused a drop in intracellular pH and

284

upregulation of sigma factors-rpoS in E. coli. Sigma factor rpoS upregulates the

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production of GadB and GadC, which are important proteins in bacterial acid

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resistance. GadB are the glutamate decarboxylases, catalyzing the proton-consuming

14

287

decarboxylation on glutamate, and GadC acted as the glutamate:4-aminobutyrate

288

antiporter to exchange the product γ-aminobutyric acid for glutamate. The

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rpoS-dependent regulation for overexpression of GadB and GadC is important to

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increase intracellular pH and to keep neutral pH during acid stress (Hope & Foster,

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2004).

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3.2. Two-component systems (TCS)

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Two-component systems (TCS) act as the general stress-response coupling

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mechanisms, which enable bacteria to sense and respond to changes in the

295

environment (Stock, And, & Goudreau, 2010). A TCS consists of a membrane-bound

296

histidine kinase for stress sensing, and a DNA-binding response regulator (RR) for the

297

regulation of DNA transcription. The phosphorylation of the sensor kinase is induced

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in response to a specific stressor, and then the phosphoryl group is transferred to and

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bind to the response regulator, which subsequently binds to the promoters and

300

initiates the transcription of the downstream genes (Fig. 2b) (Hirakawa, Nishino,

301

Hirata, & Yamaguchi, 2003). TCS has been reported to play critical roles against

302

various stimuli, such as antibiotics, osmolarity and oxidative stress (Mizuno &

303

Mizushima, 2010). For example, the EnvZ‐ OmpR is a TCS in E. coli, which has

304

been reported as an overlapping regulator in both osmolarity and

305

resistance. In the EnvZ‐ OmpR system, EnvZ is a histidine kinase and OmpR acts as

306

a transcription regulator for controlling the production of OmpF and OmpC, two porin

307

proteins in the outer membrane. The channels formed by OmpF and OmpC in the 15

-lactam antibiotic

308

outer membrane are responsible for the passive diffusion of small molecules, such as

309

salt and antibiotics. The contribution of EnvZ‐ OmpR TCS to osmolarity tolerance in

310

E. coli has been reported in many studies (Jian & Masayori, 2002; Mizuno &

311

Mizushima, 2010; Russo & Silhavy, 1991).

312

the EnvZ‐ OmpR TCS has also identified as the essential regulator for the

313

antibiotic resistance in E. coli. Hirakawa, et al. (2003) observed that the upregulation

314

of ompR conferred E. coli with two-fold increase in resistance to

315

another TCS in E. coli has been shown to be involved in stress response to both high

316

osmolarity and antibiotics (β-lactams and aminoglycosides) (Dorel, Lejeune, &

317

Rodrigue, 2006). More information about TCS in bacterial stress response can be

318

referred to the reviews of Keith (2012) and Begley & Hill (2015).

319

3.3. SOS response

320

In a study of Hirakawa, et al. (2003), -lactam

-lactam. CpxRA,

The SOS pathway is a global response for DNA damage repair pathway through

321

detection of DNA damage and expression of genes involved in DNA repair and

322

damage tolerance (Cirz, et al., 2007). SOS-mediated mechanisms are made of LexA

323

and RecA proteins. LexA is a SOS transcriptional repressor, which binds to operator

324

sites of SOS-regulated genes before the occurrence of SOS response (Simmons, Foti,

325

Cohen, & Walker, 2008). RecA can sense the presence of DNA lesions, and it

326

non-specifically bind to single-stranded DNA and lead to the auto-catalytic cleavage

327

of the LexA, subsequently causing the de-repression of SOS genes for DNA repair

328

(Gaupp, Ledala, & Somerville, 2012). SOS-mediated regulation mechanisms enable 16

329

bacteria response to a wide range of environmental stimuli, such as ultraviolet

330

radiation, toxic biomolecules, and antibiotics (Ivan, Susana, & Jordi, 2010). SOS

331

pathway might be another overlapping response against antibiotics and

332

food-associated stresses. Cirz, et al. (2007) found that UV pretreatment (8.6 J/m2)

333

could induce DNA damage in S. aureus, which evoked the SOS-mediated DNA repair

334

regulation. The inhibition of DNA transcription or protein synthesis during SOS

335

response might render the resistance to streptomycin and rifampin, of which targets

336

are ribosomes and the DNA-dependent RNA polymerase. SOS-mediated antibiotic

337

resistance was also observed in E. coli and Pseudomonas aeruginosa (Cirz, O'Neill,

338

Hammond, Head, & Romesberg, 2006; Tatiana, et al., 2005). In addition to antibiotics,

339

SOS response is also induced in bacteria as a response against other external stimuli.

340

High pressure, a nonthermal sterilization technology in food industry, has been shown

341

to induce the SOS response in E. coli (Abram, Rob, Kristof, & Michiels, 2004). It is

342

reported that high pressure (100 MPa) triggered the activation of an endogenous

343

restriction endonuclease Mrr, which resulted in a double strand break and induced the

344

initiation of SOS response (Abram & Michiels, 2010). Thus, the preexposure of high

345

pressure might bring out a cross protection for bacteria against the following

346

antibiotic treatment.

347

3.4. Efflux pumps

348 349

One of the essential mechanisms for bacterial antibiotic resistance relies on efflux pumps, which consist of five protein families of efflux pumps, including the 17

350

multidrug and toxic-compound extrusion (MATE) family, the major facilitator

351

superfamily (MFS), the resistance nodulation division (RND) family, the ATP-

352

binding cassette (ABC) superfamily, and the small multidrug resistance (SMR) family

353

(Keith, 2009; Sylvain, Marc, Guy, Christine, & Patrice, 2003). Efflux pumps actively

354

extrude antibiotics from bacterial cells to resist their lethal effects. Efflux pumps are

355

also shown to be capable of expelling other toxic stimuli out in response to stress. The

356

summary for the overlapping efflux pumps for the antibiotic resistance and tolerance

357

towards food-associated stresses is exhibited in Table 4. Zhu & Dai (2018) found that

358

exposure to high salt could upregulate the expression of AcrAB-TolC multidrug

359

efflux pump in E. coli. The TolC is the channel in outer membranes, and AcrB and

360

AcrA locate in inner membrane and the periplasm, respectively. AcrAB-TolC efflux

361

assembly is responsible for pumping antibiotics out to decrease their accumulation.

362

The expression of AcrAB-TolC can explain the increased antibiotic resistance of E.

363

coli to the following antibiotic stress of tetracycline and chloramphenicol after

364

exposure to high salt. Komora, et al. (2017) found that the inhibition of efflux pumps

365

with reserpine and thioriodazine in antibiotic resistant L. monocytogenes decreased

366

the MIC of disinfectants-hydrogen peroxide and benzalkonium chloride by two to

367

eight folds. Yu, et al. (2018) also found that a multidrug resistance pump MdrL

368

belonging to MFS family is critical for the tolerance of L. monocytogenes to

369

benzalkonium chloride. Defection in mdrL impaired the growth of L. monocytogenes

370

in the presence of benzalkonium chloride. MdrL in L. monocytogenes has been

18

371

reported for developing the resistance against macrolides and cefotaxime (Mata,

372

Baquero, & Perez-Diaz, 2000). Similarly, a study by Potenski, et al. (2010) identified

373

that the pretreatment of Salmonella Enteritidis with chlorine or other preservatives

374

such as sodium nitrite, sodium benzoate or acetic acid induced the overexpression of

375

marRAB operon, a global antibiotic resistance regulator which involved in the

376

production of AcrAB efflux pumps to extrude antibiotics.

377

3.5. Other mechanisms

378

Mutations have been indicated as a strategy for bacteria to develop the antibiotic

379

resistance (Blair, Webber, Baylay, Ogbolu, & Piddock, 2015). Such mutations might

380

also confer cross-protection to other stresses. Gomez, et al. (2017) confirmed that the

381

ribosomal mutations in rplO, rplF, rplE and rplY during adaptation to ciprofloxacin

382

contributed cross-resistance to thermal pressure (54 ̊C, 2 h). Ribosomal mutations

383

induced by the antibiotic adaptation might affect cell translation and subsequently

384

sensed by bacterial cells to cause large changes in the overall transcriptome. In a

385

study by Kim, et al. (2018), benzalkonium chloride disinfectants were found to

386

enhance the resistance of P. aeruginosa to polymyxin B through the mutation

387

selection mechanisms. The exposure of benzalkonium chloride is responsible for

388

selecting the cells with pmrB mutations, which has been confirmed to increase the

389

resistance to polymyxin B. The selection effect of the preliminary stress could confer

390

cross protection to the following stressors. In addition, the modification in antibiotic

391

binding sites in bacterial cell membranes was observed to be induced by other

19

392

stressors, which can be employed for the cross protection to antibiotics.

393

Rahmati-Bahram, Magee, & Jackson (1997) found that higher temperature induced

394

higher extents of esterification in the aminoglycoside binding

395

targets-lipopolysaccharide (LPS), which decreased the binding to aminoglycoside and

396

increased the antibiotic resistance. Also, the down-regulation of penicillin binding

397

proteins for cell wall synthesis during cold, acid and osmotic stress might be another

398

cross protection mechanism through inactivation of target for

399

thus enhancing the development of antibiotic resistance (Al-Nabulsi, et al., 2015).

400

4. Conclusions and future perspectives

-lactamase antibiotics,

401

Food chain has been considered as a major vehicle for the dissemination of

402

antibiotic resistant bacteria. Diverse stress during food processing might act as drivers

403

to exacerbate the challenge of antibiotic resistance through cross protection

404

mechanisms (Fig. 3). This review provides a comprehensive overview for the

405

interplay between antibiotic resistance and food-associated stress tolerance in bacteria.

406

Many of the reference studies mentioned in this work show that some commonly used

407

food processing methods such as heating, acidification, osmosis and novel nonthermal

408

technologies can sharpen the resistance of pathogenic bacteria in foods to a range of

409

currently used antibiotics, and vice versa which poses potential risk to food safety and

410

human health. Therefore, cross protection phenomenon should be taken into

411

consideration when designing and implementing various food processing methods. In

412

addition, we have hypothesized molecular mechanisms of cross protection between 20

413

antibiotics and food-associated stresses in this manuscript. However, so far, the

414

research in this filed is still inconclusive. Various results from various studies might

415

be related to the differences in bacterial strains and stress conditions. Better

416

understanding is required to reveal the behavior of bacteria linking antibiotic

417

resistance and tolerance to food-associated stresses.

418 419 420 421

Acknowledgement This study was supported by the National Key Research and Development Program of China (2016YFD0400301)

422 423

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Zhang, C. M., Xu, L. M., Wang, X. C., Zhuang, K., & Liu, Q. Q. (2017). Effects of

704

ultraviolet disinfection on antibiotic‐ resistant Escherichia coli from

705

wastewater: inactivation, antibiotic resistance profiles and antibiotic resistance

706

genes. Journal of Applied Microbiology, 123.

707 708

Zhu, M., & Dai, X. (2018). High salt cross-protects Escherichia coli from antibiotic treatment through increasing efflux pump expression. Msphere, 7.

709 710 711 712 713 714 715 716

35

717 718 719 720 721 722 723 724 725

36

726

Figure captions

727

Fig. 1 Examples of how antibiotic resistance genes spread

728

Fig. 2 Overview of sigma factor-dependent stress response (a) and two-component

729

system (TCS)-dependent stress response (b).

730

Fig. 3 The mechanisms of cross protection between antibiotics and food-associated

731

stresses.

732

733

734

735

37

1

Table captions

2

Table 1. Stress conditions that may induce stress resistance in foodborne pathogens

3

during food processing, preservation and storage (Begley & Hill, 2015).

Stress

Stage in food production

Heat

Cooking of food, food processing

Acidification (low pH)

fermentation, food processing

Osmotic pressure

Addition of additives such as NaCl

Oxidation

Addition of oxidative sanitizers, Food processing (hot air drying,

Dehydration freeze-drying, vaccum) High hydrostatic pressure

Food processing

Preservatives

Food processing

Irradiation

Food preservation (UV, γ rays, X rays)

Sanitizers (e.g., quaternary ammonium compounds, benzalkonium

Food processing

chloride, electrolyzed water, chlorine) Oxygen reduction (e.g., modified atmospheric packaging, vacuum

Food preservation

packaging)

1

Bacteriocins (e.g., nisin)

Food preservation

2

4

Table 2. The effect of antibiotic resistance on the tolerance to food associated stresses of bacteria. Food-associated Antibiotic resistance

Cross Mediums

Strains

stresses

References protection

Yersinia Heat

Minced beef and

enterocolitica，

No

Nalidixic acid

(Doherty, et al., 2010) (50-60℃)

potato

Listeria monocytogenes

Heat

Minced beef and

Listeria

Streptomycin (55℃) Erythromycin, ciprofloxacin and

potato

Heat (58℃)

Nalidixic acid

Heat

(Walsh, et al., 2010)

No

(Komora, et al., 2017)

No

(Dombroski, et al.,

monocytogenes Listeria

Ringer's solution nitrofurantoin

NO

monocytogenes Oysters

3

Vibrio vulnificus

(50℃)

1999)

Ampicillin, kanamycin, streptomycin, trimethoprim, nalidixic acid, rifampicin, Heat sulphonamides, chloramphenicol,

Escherichia coli minced meat

(55℃)

O157:H7

Heat

Staphylococcus

No

(Duffy, et al., 2006)

No

(Ma, et al., 2019)

Yes

(Gomez, et al., 2017)

chloramphenicol, tetracycline, minocycline, doxycycline Ciprofloxacin, chloramphenicol, erythromycin, penicillin, sulfamethoxazole, clindamycin,

Saline solution (63℃)

aureus

tetracycline, oxacillin, cefoxitin, gentamicin Ciprofloxacin

Heat

Middlebrook 7H9

4

Mycobacterium

(54℃)

medium (M7H9)

Heat

smegmatis Escherichia coli

Trimethoprim, ampicillin, ofloxacin

TSB (56℃)

(Azizoglu & Drake, No

O157:H7

2007)

sterile potassium Erythromycin, ciprofloxacin and

Osmosis

Listeria phosphate buffer

nitrofurantoin

(37% NaCl)

Yes

(Komora, et al., 2017)

Yes

(Ma, et al., 2019)

NO

(D'AMICO, Druart, &

monocytogenes added by NaCl

Ciprofloxacin, chloramphenicol, erythromycin, penicillin, Osmosis

Saline solution

Staphylococcus

sulfamethoxazole, clindamycin, (30% NaCl)

with NaCl

aureus

Salt in moisture

Gouda cheese

Salmonella

tetracycline, oxacillin, cefoxitin, and gentamicin amoxicillin–clavulanic acid; ampicillin;

5

cefoxotin; ceftiofur; chloramphenicol;

phase (3.88%)

Donnelly, 2014)

kanamycin; streptomycin; sulfisoxazole; tetracycline; ceftriaxone. erythromycin, ciprofloxacin and

Acid

Sterile potassium

Listeria yes

nitrofurantoin

(1% lactic acid)

phosphate buffer

monocytogenes

Acid

Saline solution

Staphylococcus

(Komora, et al., 2017)

Ciprofloxacin, chloramphenicol, erythromycin, penicillin, Yes

sulfamethoxazole, clindamycin,

(Ma, et al., 2019) (HCl, pH 1.5)

with NaCl

aureus

M9 medium

Escherichia coli

tetracycline, oxacillin, cefoxitin, and gentamicin Acid Trimethoprim (HCl pH 3)

6

Yes

(Mitosch, et al., 2017)

Ampicillin, kanamycin, streptomycin, Natural yoghurt Trimethoprim, nalidixic acid, rifampicin, (∼ pH 4.2),

Yogurt, low pH

Escherichia coli NO

sulphonamides, chloramphenicol, Fresh orange juice

juices

(Duffy, et al., 2006)

O157:H7

chloramphenicol, tetracycline, (∼ pH 4.4) minocycline, doxycycline Acid Escherichia coli Trimethoprim, ampicillin, ofloxacin

(Simulated gastric

TSB

(Azizoglu & Drake, No

O157:H7

2007)

fluid, pH 1.5) a combination of amoxicillin and clavulanic acid; ampicillin; a combination of ampicillin and sulbactam; ceftriaxone; chloramphenicol; ciprooxacin; enrooxacin;

Acetic acid (2%), lactic acid (2%), and FreshFX

Minimal E (Bacon, Sofos,

medium containing 0.4% glucose

(pH 1.5)

7

Salmonella

NO

Kendall, Belk, & Smith, 2003)

gentamicin; levooxacin; streptomycin; sulfonamides; tetracycline; a combination of trimethoprim

and sulfamethoxazole Lactic acid (3%) Ground beef and

Ampicillinn, chloramphenicol, Acid (Acidified streptomycin, sulfon- amides,

freshly harvested

Salmonella

NO

(Hughes, et al., 2010)

NO

(Cunha, et al., 2016)

sodium chloride, tetracyclines, cephalosporins

beef briskets 100 ppm)

erythromycin, ciprofloxacin and

Gastrintestinal

Listeria

Acid (HCl pH 2.5) nitrofurantoin

tract

monocytogenes

Amoxicillin–clavulanic acid; ampicillin; (D'AMICO, et al., cefoxotin; ceftiofur; chloramphenicol;

Gouda cheese

Salmonella

NO 2014)

kanamycin; streptomycin; sulfisoxazole;

8

tetracycline; ceftriaxone. Oasis-146⃝R, Multi-Quat Stainless steel Rifampicin

Sanitizer,

Vortexx⃝R

(Fouladkhah, et al., Salmonella

No

coupons

2013)

-Acid Liquid Sanitizer tetracycline, sulfamethoxazole, ampicillin, gentamicin, streptomycin, cefotaxime,

Ultraviolet (UV) Escherichia coli 2

(20 mJ/cm )

Wastewater

Yes

(Zhang, et al., 2017)

Yes (chlorine)

(Templeton, et al.,

No (UV)

2009)

chloramphenicol, ciprofloxacin, norfloxacin Chlorine (Cl2, 100 Trimethoprim

mg/L)

Deionized water

9

Escherichia coli

UV doses (0, 1, 3, and 5 mJ/cm2) Chlorination (Cl2, Tetracycline

0-8 mg/L)

Potassium

Escherichia coli

Yes (chlorine) (Huang, et al., 2013)

UV doses (0-80

phosphate buffer

mJ/cm2) 5 6 7 8 9 10

10

No (UV)

11 12

Table 3. The effect of food-associated stress tolerance on antibiotic resistance profile of bacteria. Food-associated stress

Antibiotic

Mediums

Strains

Cross protection

References

Amikacin, norfloxacin, piperacillin, Heat (45℃)

Acinetobacter BHI

(Ebinesh, et al., Yes

tazobactam, imipenem,

baumannii

2018)

meropenem Amikacin, ceftriaxone,

Escherichia coli

nalidixic acid (for

Salmonella enterica

Heat

(Mcmahon, et al., Escherichia coli);

MHB

serovar

(45℃)

No 2007)

Amikacin, ceftriaxone,

Typhimurium

trimethoprim (for

Staphylococcus

11

Salmonella); Amikacin,

aureus

ceftriaxone, trimethoprim (for S. aureus) Amikacin, norfloxacin, Sterile potassium Cold

piperacillin,

Cronobacter phosphate buffer

(5℃)

(Anas A Al-Nabulsi, Yes

tazobactam, imipenem,

sakazakii

et al., 2011)i

Listeria

(Anas A. Al-Nabulsi,

meropenem Cold

Streptomycin,

Sterile potassium

Yes (10℃)

gentamycin, ampicillin,

phosphate buffer

monocytogenes

12

et al., 2015)

penicillin, tetracycline,

Osmosis

doxycycline, vancomycin,

(2, 4, 6,12% NaCl)

Yes

ciprofloxacin and enrofloxaci

High salt condition

Tetracycline, Escherichia coli

(0.4 M NaCl)

chloramphenicol

Acid

Ampicillin, tetracycline,

Potassium phosphate

(Lactic acid,

pH 6.0, 5.5, 5.0)

vancomycin

Acid

Streptomycin,

(Zhu & Dai, 2018)

(Anas A. Al-Nabulsi, L. monocytogenes

doxycycline and

Yes

Yes

buffer

et al., 2015)

Potassium phosphate

13

Cronobacter

No (streptomycin,

(Anas A Al-Nabulsi,

(pH 3.5 with 85%

gentamicin, kanamycin

lactic acid)

and doxycycline

buffer

sakazakii

gentamicin, kanamycin and doxycycline) Yes (tetracycline, tilmicosin, florfenicol, amoxicillin, ampicillin, vancomycin and neomycin, ciprofloxacin, and enrofloxacin)

14

et al., 2011)

Tetracycline, chloramphenicol, ampicillin and penicillin, cephalosporins Human simulated

Esophagus-stomach ceftriaxone, cefepime,

(De Sales, et al., gastrointestinal

conditions (HCl, pH

Salmonella

2018)

kanamycin, gentamicin; condition

2.0 - 3.8)

YES

ciprofloxacin, the combination sulfamethoxazole and trimethoprim, cyclic lipopeptide polymyxin

15

B Cefuroxime, Acid

ceftazidime, cefepime,

(Sulphuric acid, pH 3

amikacin, norfloxacin,

BHI

Acinetobacter

(Ebinesh, et al., Yes

-6)

imipenem, meropenem,

baumannii

2018)

ampicillin+sulbactam, piperacillin+tazobactam Benzalkonium

Cefotaxime, BHI

Chloride (EtBr)

Listeria

cephalothin,

Yes

(Yu, et al., 2018)

monocytogenes ciprofloxacin A quaternary

Chloramphenicol,

(Karatzas, et al., LB broth

ammonium

Salmonella

tetracycline, ampicillin,

Yes 2007)

16

disinfectant

acriflavine and triclosan

(formaldehyde and glutaraldehyde, QACFG) Aldehyde based disinfectant (ABD,

Ciprofloxacin

LB broth

Salmonella

PBS

Salmonella

Yes

(Randall, et al., 2007)

0.025%, v/v) Tetracycline, Sanitizers (Chlorine, chloramphenicol,

(Potenski, et al., Yes

sodium nitrite，sodium nalidixic acid, and

2010)

benzoate) ciprofloxacin Gamma irradiation and

Penicillin, ampicillin,

Salmon fillets

Listeria

17

Yes

(Skowron, et al.,

electron beam

meropenem,

monocytogenes

2018)

erythromycin and trimethoprim‐ sulfamethoxazole

Cephalexin

Culture

Klebsiella

Yes (Klebsiella

pneumonia

pneumonia)

Staphylococcus

No (Staphylococcus (Skowron, et al.,

Ultrasound

epidermidis,

epidermidis, 2018)

Nonthermal plasma,

Tetracycline,

Sterile

18

Staphylococcus

Staphylococcus

aureus and

aureus and

Salmonella

Salmonella)

Staphylococcus

No

(Guo, et al., 2018)

plasma-activated water

gentamycin,

(PAW)

clindamycin,

saline solution

aureus

Broth medium

Klebsiella

chloramphenicol, ciprofloxacin, rifampicin, vancomycin Aztreonam, Irradiation (2.4 GHz)

cefteriaxone, imipenem,

No

(Taheri, et al., 2015)

pneumonia piperacilline, cefotaxime Low-frequency

Escherichia coli kanamycin

Medium

(Segatore, et al., No

electromagnetic fields

ATCC 25922，

19

2012)

(2 mT; 50 Hz)

Pseudomonas aeruginosa ATCC 27853

13 14 15 16 17 18 19 20 21 22

20

23

Table 4. Overlapping efflux pumps for antibiotic resistance and tolerance to food-associated stresses. Efflux pumps

Strains

Antibiotic

Food-associated stresses

References (Rosenberg, et al., 2010;

Escherichia coli

Osmolarity Zhu & Dai, 2018)

AcrAB (RND

Tetracycline, A blend of high boiling

family)/TolC

Salmonella

Chloramphenicol point tar acids and organic

(Randall, et al., 2007)

acids MdrL

(Komora, et al., 2017; Erythromycin

(MFS family) Listeria monocytogenes Lde

Benzalkonium chloride,

Romanova, Wolffs, &

Hydrogen peroxide,

Brovko, 2006; Yu, et al., 2018)

Fluoroquinolones (MFS family)

21

AnrAB β-Lactam antibiotics (ATP-binding cassette

Listeria monocytogenes

(Collins, Curtis, Cotter, Nisin Hill, & Ross, 2010)

family, ABC) tetracycline or MarRAB Salmonella

chloramphenicol

Chlorine, sodium nitrite, sodium benzoate, acetic

(Potenski, et al., 2010)

(MarR family) acid EmrB (MEF family)/

Nalidixic acid (Deininger, et al., 2011;

TolC，

Escherichia coli

（EmrB/ TolC） Acid

Koronakis, Eswaran, &

β-Lactam antibiotics

MdtB (RND family)/

Hughes, 2004) TolC

AcrAB (RND family)

（MdtB / TolC） Moraxella catarrhalis

Amoxicillin, cefotaxime,

(Spaniol, Bernhard, & Cold

clarithromycin

22

Aebi, 2015)

-OprM Pseudomonas

Fluoroquinolones,

MexCD-OprJ

Benzalkonium Chloride aeruginosa

Tetracycline

24 25

23

(Kim, et al., 2018)

1

Figures

2

Fig. 1

3 4

Fig. 2

5 6

(a)

7 8

(b)

1

9

Fig. 3 Cross-protection Antibiotics

Food-associated stresses General stress response Sigma factors Two-component system (TCS) SOS pathway

Antibiotic resistance Efflux pumps Mutation Binding target modification …

10 11

12

13

14

2

Tolerance to heat, cold, acids, osmolarity, nonthermal methods…

Highlights The dissemination of antibiotic resistance through food chain. Linked microbial antibiotic-resistance to food-associated stresses. Mechanisms of microbial cross protection to antibiotics and other stresses.