Antibiotic resistance in Vibrio cholerae: Understanding the ecology of resistance genes and mechanisms

Das, Bhabatosh; Verma, Jyoti; Kumar, Promod; Ghosh, Amit; Ramamurthy, Thandavarayan

doi:10.1016/j.vaccine.2019.06.031

Cited by 145 publications

(141 citation statements)

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“…However, emergence of antibiotic resistance (AMR) and rapid dissemination of resistant traits in the clinically important bacterial species has drastically reduced the efficacy of several therapeutic agents commonly used to prevent or treat microbial infection ( Das et al, 2017 ). AMR could be intrinsic or acquired and a wide range of metabolic pathways can confer resistance phenotype in bacteria ( Figure 4 ; Das et al, 2020 ). Horizontal gene transfer (HGT), de novo mutation and changes in the expression profile of secreted proteins determine the rate of emergence of resistant variants ( Davies and Davies, 2010 ).…”

Section: Bodymentioning

confidence: 99%

“…From various studies, it appears that emergence of instant antibiotic resistant clones in a susceptible bacterial population solely depends on: (i) target modifications, (ii) reduced accessibility of antibiotics to the target, (iii) decreased effective concentration of antibiotic by reducing the membrane permeability or by increasing efflux activity, and (iv) acquisition of antibiotic resistance genes from other microbial species ( Gaca et al, 2015 ; Verma et al, 2019 ; Das et al, 2020 ; Jung et al, 2020 ; Pant et al, 2020 ). A recent study has shown that the expression levels of ~300 and ~400 genes (total ~700 genes) are upregulated and downregulated, respectively, within 5 min upon induction of (p)ppGpp ( Sanchez-Vazquez, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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(p)ppGpp Metabolism and Antimicrobial Resistance in Bacterial Pathogens

Das

Bhadra

2020

Front. Microbiol.

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Single cell microorganisms including pathogens relentlessly face myriads of physicochemical stresses in their living environment. In order to survive and multiply under such unfavorable conditions, microbes have evolved with complex genetic networks, which allow them to sense and respond against these stresses. Stringent response is one such adaptive mechanism where bacteria can survive under nutrient starvation and other related stresses. The effector molecules for the stringent response are guanosine-5'-triphosphate 3'-diphosphate (pppGpp) and guanosine-3', 5'-bis(diphosphate) (ppGpp), together called (p)ppGpp. These effector molecules are now emerging as master regulators for several physiological processes of bacteria including virulence, persistence, and antimicrobial resistance. (p)ppGpp may work independently or along with its cofactor DksA to modulate the activities of its prime target RNA polymerase and other metabolic enzymes, which are involved in different biosynthetic pathways. Enzymes involved in (p)ppGpp metabolisms are ubiquitously present in bacteria and categorized them into three classes, i.e., canonical (p)ppGpp synthetase (RelA), (p)ppGpp hydrolase/synthetase (SpoT/Rel/RSH), and small alarmone synthetases (SAS). While RelA gets activated in response to amino acid starvation, enzymes belonging to SpoT/Rel/RSH and SAS family can synthesize (p)ppGpp in response to glucose starvation and several other stress conditions. In this review, we will discuss about the current status of the following aspects: (i) diversity of (p)ppGpp biosynthetic enzymes among different bacterial species including enteropathogens, (ii) signals that modulate the activity of (p)ppGpp synthetase and hydrolase, (iii) effect of (p)ppGpp in the production of antibiotics, and (iv) role of (p)ppGpp in the emergence of antibiotic resistant pathogens. Emphasis has been given to the cholera pathogen Vibrio cholerae due to its sophisticated and complex (p)ppGpp metabolic pathways, rapid mutational rate, and acquisition of antimicrobial resistance determinants through horizontal gene transfer. Finally, we discuss the prospect of (p)ppGpp metabolic enzymes as potential targets for developing antibiotic adjuvants and tackling persistence of infections.

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Section: Bodymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

(p)ppGpp Metabolism and Antimicrobial Resistance in Bacterial Pathogens

Das

Bhadra

2020

Front. Microbiol.

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“…The emergence of antimicrobial resistance among Vibrio cholerae is a burden on public health especially in developing countries (Das et al, 2019). An increase in the incidence of multidrug resistance V. cholerae could hurt cholera-controlling measures within a community (Mushayabasa and Bhunu, 2012).…”

Section: Discussionmentioning

confidence: 99%

Exploration of Anti-infectives From Mangrove-Derived Micromonospora sp. RMA46 to Combat Vibrio cholerae Pathogenesis

et al. 2020

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Vibrio cholerae, the etiological agent of cholera, employs quorum sensing (QS) pathways to control the expression of virulence factors, including the production of cholera toxin and biofilm formation. Acquired antibiotic resistance in V. cholerae draws attention to the development of novel therapeutics that counteract virulence, rather than the viability of the pathogen. In this context, we explored the anti-infective potential of rare marine Actinobacteria (RMA) from a mangrove ecosystem. Here, we report the effects of Micromonospora sp. RMA46 against V. cholerae in vitro. The RMA46 organic extract was non-bactericidal to V. cholerae cells and non-cytotoxic to macrophage RAW264.7 cell lines. RMA46 inhibited the formation of V. cholerae biofilms and downregulated the QS global switches LuxO and HapR, as well as other virulence genes including ct, tcp, and hapA. In silico molecular docking simulation of RMA46 ethyl acetate extract with LuxO and HapR revealed that 2-methoxy-4-vinylphenol and hexahydro-3-(phenylmethyl)-pyrrolo[1,2-a]pyrazine-1,4-dione could interact with the active sites of LuxO and HapR and potentially inhibit them. This study highlights Micromonospora sp. RMA46 as a potential source of anti-infectives against V. cholerae.

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“…The contributing factors towards this increasing antibiotic resistance include chromosomal mutations, export of the antibiotics outside the cell through efflux pumps, and attaining genetic resistance through the exchange of plasmids, transposons, SXT elements, and autonomously replicating and integrating plasmids or integrons (Kumar et al, 2009;Kitaoka et al, 2011a;Verma et al, 2019). Integrating conjugative elements (ICE) and superintegrons from closely or distinctly related bacteriums are the major causes of antimicrobial resistance in V. cholerae (Verma et al, 2019;Das et al, 2020). Various strategies have been enforced to comabat these MDR strains, including the usage of various efflux pump inhibitors and quorum sensing inhibitors, but the problem remains unsolved (Hema et al, 2016;Lowrence et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Exploring Computational and Biophysical Tools to Study the Presence of G-Quadruplex Structures: A Promising Therapeutic Solution for Drug-Resistant Vibrio cholerae

et al. 2020

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Vibrio cholerae, a gram-negative bacterium that causes cholera, has already caused seven major pandemics across the world and infects roughly 1.3-4 million people every year. Cholera treatment primarily involves oral rehydration therapy supplemented with antibiotics. But recently, multidrug-resistant strains of V. cholerae have emerged. High genomic plasticity further enhances the pathogenesis of this human pathogen. Guanines in DNA or RNA assemble to form G-quadruplex (GQ) structures which have begun to be seen as potential drug targeting sites for different pathogenic bacteria and viruses. In this perspective, we carried out a genome-wide hunt in V. cholerae using a bio-informatics approach and observed ∼85 G-quadruplex forming motifs (VC-PGQs) in chromosome I and ∼45 putative G-quadruplexs (PGQs) in chromosome II. Ten putative G-quadruplex forming motifs (VC-PGQs) were selected on the basis of conservation throughout the genus and functional analysis displayed their location in the essential genes encoding bacterial proteins, for example, methyl-accepting chemotaxis protein, orotate phosphoribosyl transferase protein, amidase proteins, etc. The predicted VC-PGQs were validated using different bio-physical techniques, including Nuclear Magnetic Resonance spectroscopy, Circular Dichroism spectroscopy, and electrophoretic mobility shift assay, which demonstrated the formation of highly stable GQ structures in the bacteria. The interaction of these VC-PGQs with the known specific GQ ligand, TMPyP4, was analyzed using ITC and molecular dynamics studies that displayed the stabilization of the VC-PGQs by the GQ ligands and thus represents a potential therapeutic strategy against this enteric pathogen by inhibiting the PGQ harboring gene expression, thereby inhibiting the bacterial growth and virulence. In summary, this study reveals the presence of conserved GQ forming motifs in the V. cholerae genome that has the potential to be used to treat the multi-drug resistance problem of the notorious enteric pathogen.

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Antibiotic resistance in Vibrio cholerae: Understanding the ecology of resistance genes and mechanisms

Cited by 145 publications

References 93 publications

(p)ppGpp Metabolism and Antimicrobial Resistance in Bacterial Pathogens

(p)ppGpp Metabolism and Antimicrobial Resistance in Bacterial Pathogens

Exploration of Anti-infectives From Mangrove-Derived Micromonospora sp. RMA46 to Combat Vibrio cholerae Pathogenesis

Exploring Computational and Biophysical Tools to Study the Presence of G-Quadruplex Structures: A Promising Therapeutic Solution for Drug-Resistant Vibrio cholerae

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