Bacterial Multidrug Efflux Pumps of the Major Facilitator Superfamily as Targets for Modulation

Kumar, Sanath; He, Guojin; Kakarla, Prathusha; Shrestha, Ugina; Ranjana, KC; Ranaweera, Indrika; Willmon, T. Mark; Barr, Sharla R.; Hernández, A.; Várela, M.

doi:10.2174/1871526516666160108115034

Cited by 5 publications

(5 citation statements)

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“…Reserpine was first reported to inhibit MDR transporter, Bmr from Bacillus subtilis (Neyfakh et al ). The MDR pumps of Staphylococcus aureus , that is, NorA, LmrS and MdeA; Lde of Listeria monocytogenes have also been reported to be inhibited by reserpine (Godreuil et al ; Floyd et al ; Kumar et al ). However, there is no such report for closely related homologues of STY4874 including MdfA and MdtM of E. coli .…”

Section: Resultsmentioning

confidence: 99%

Restraining the multidrug efflux transporter STY4874 of Salmonella Typhi by reserpine and plant extracts

Tariq

Sana

Shaheen

et al. 2019

Lett Appl Microbiol

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Efflux‐mediated multidrug resistance is a well‐known phenomenon facilitated by multidrug resistant (MDR) transporters. One of the approaches to counteract efflux‐mediated resistance is the use of MDR pump inhibitors, and thus be used in combination with the conventional antibiotics to treat deadly diseases like typhoid fever. We have previously reported that STY4874, an efflux transporter of Salmonella serotype Typhi, exhibited promising characteristics as MDR pump. In this study, we aimed to get an insight into possible STY4874 inhibitors of plant origin. STY4874 was overexpressed in Escherichia coli and extracts from pomegranate peel, milk thistle seeds and reserpine, a synthetic plant alkaloid, were screened for inhibition of ciprofloxacin efflux. The extracts of milk thistle seeds and reserpine when incubated with ciprofloxacin showed statistically significant STY4874‐mediated inhibitory activity, rendering the efflux pump inactive and hence early growth inhibition of host cells compared with cells expressing efflux pump and incubated only with ciprofloxacin. This efflux pump inhibitory activity was further confirmed by time‐kill experiments. This study is the first to report on efflux pump inhibition of S. Typhi STY4874 and results can be extended towards its close homologues such as MdfA and MdtM from E. coli. Significance and Impact of the Study Understanding and combating resistance governed by multidrug efflux transporters is an ongoing research intensive area, affecting treatment of various nosocomial and endemic/epidemic infections. Confronting drug resistance requires that inhibitors debilitating the underlying mechanisms should be included in combination therapy. One such example is the prescription of clavulanic acid as combination therapy with amoxicillin, collectively called as co‐amoxiclav to combat β‐lactamase‐mediated resistance. However, research related to finding the inhibitors of efflux transporters, the resistance mechanism distinct from β‐lactamase mediated resistance is at an early stage. The current study finds that plant‐derived inhibitors can be an option towards restraining efflux‐mediated resistance.

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Section: Resultsmentioning

confidence: 99%

Restraining the multidrug efflux transporter STY4874 of Salmonella Typhi by reserpine and plant extracts

Tariq

Sana

Shaheen

et al. 2019

Lett Appl Microbiol

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“…It can be hypothesized that the presence of a large number of multidrug resistance proteins and their expression have facilitated the evaluation of the pathogen to adopt mechanisms to demonstrate broad spectrum antibiotic resistance. 169,170…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of Hypothetical Proteins of Vibrio parahaemolyticus Reveals the Presence of Virulence Factors and Growth-Related Enzymes With Therapeutic Potential

Shahrear

Zinnia

Sany

et al. 2022

Bioinform Biol Insights

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Vibrio parahaemolyticus, an aquatic pathogen, is a major concern in the shrimp aquaculture industry. Several strains of this pathogen are responsible for causing acute hepatopancreatic necrosis disease as well as other serious illness, both of which result in severe economic losses. The genome sequence of two pathogenic strains of V. parahaemolyticus, MSR16 and MSR17, isolated from Bangladesh, have been reported to gain a better understanding of their diversity and virulence. However, the prevalence of hypothetical proteins (HPs) makes it challenging to obtain a comprehensive understanding of the pathogenesis of V. parahaemolyticus. The aim of the present study is to provide a functional annotation of the HPs to elucidate their role in pathogenesis employing several in silico tools. The exploration of protein domains and families, similarity searches against proteins with known function, gene ontology enrichment, along with protein-protein interaction analysis of the HPs led to the functional assignment with a high level of confidence for 656 proteins out of a pool of 2631 proteins. The in silico approach used in this study was important for accurately assigning function to HPs and inferring interactions with proteins with previously described functions. The HPs with function predicted were categorized into various groups such as enzymes involved in small-compound biosynthesis pathway, iron binding proteins, antibiotics resistance proteins, and other proteins. Several proteins with potential druggability were identified among them. In addition, the HPs were investigated in search of virulent factors, which led to the identification of proteins that have the potential to be exploited as vaccine candidate. The findings of the study will be effective in gaining a better understanding of the molecular mechanisms of bacterial pathogenesis. They may also provide an insight into the process of evaluating promising targets for the development of drugs and vaccines against V. parahaemolyticus.

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“…In 2017, our laboratory discovered that garlic extract from Allium sativum and its bioactive agent allyl sulfide inhibited the antimicrobial efflux activity of EmrD-3 from V. cholerae [113], indicating that the EmrD-3 multidrug efflux pump is a good target for resistance modulation and inhibition of growth for the cholera pathogen [59,114,115]. Furthermore, we showed that elements of A. sativum extract exhibited profound synergy when combined with clinically critical antimicrobial agents, like lincomycin, vancomycin, and others [113].…”

Section: Efflux Pumps Of Mfs Family In Vibrio Speciesmentioning

confidence: 99%

Membrane Efflux Pumps of Pathogenic Vibrio Species: Role in Antimicrobial Resistance and Virulence

et al. 2022

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Infectious diseases caused by bacterial species of the Vibrio genus have had considerable significance upon human health for centuries. V. cholerae is the causative microbial agent of cholera, a severe ailment characterized by profuse watery diarrhea, a condition associated with epidemics, and seven great historical pandemics. V. parahaemolyticus causes wound infection and watery diarrhea, while V. vulnificus can cause wound infections and septicemia. Species of the Vibrio genus with resistance to multiple antimicrobials have been a significant health concern for several decades. Mechanisms of antimicrobial resistance machinery in Vibrio spp. include biofilm formation, drug inactivation, target protection, antimicrobial permeability reduction, and active antimicrobial efflux. Integral membrane-bound active antimicrobial efflux pump systems include primary and secondary transporters, members of which belong to closely related protein superfamilies. The RND (resistance-nodulation-division) pumps, the MFS (major facilitator superfamily) transporters, and the ABC superfamily of efflux pumps constitute significant drug transporters for investigation. In this review, we explore these antimicrobial transport systems in the context of Vibrio spp. pathogenesis and virulence.

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Bacterial Multidrug Efflux Pumps of the Major Facilitator Superfamily as Targets for Modulation

Cited by 5 publications

References 0 publications

Restraining the multidrug efflux transporter STY4874 of Salmonella Typhi by reserpine and plant extracts

Restraining the multidrug efflux transporter STY4874 of Salmonella Typhi by reserpine and plant extracts

Functional Analysis of Hypothetical Proteins of Vibrio parahaemolyticus Reveals the Presence of Virulence Factors and Growth-Related Enzymes With Therapeutic Potential

Membrane Efflux Pumps of Pathogenic Vibrio Species: Role in Antimicrobial Resistance and Virulence

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