Abstract
Vibrio cholerae encodes six resistance-nodulation-division (RND) efflux systems which function in antimicrobial resistance, virulence factor production, and intestinal colonization. Among the six RND efflux systems, VexAB exhibited broad substrate specificity and played a predominant role in intrinsic antimicrobial resistance. The VexAB system was encoded in an apparent three gene operon that included vexR; which encodes an uncharacterized TetR family regulator. In this work we examined the role of vexR in vexRAB expression. We found that VexR bound to the vexRAB promoter and vexR deletion resulted in decreased vexRAB expression and increased susceptibility to VexAB antimicrobial substrates. Substrate-dependent induction of vexRAB was dependent on vexR and episomal vexR expression provided a growth advantage in the presence of the VexAB substrate deoxycholate. The expression of vexRAB increased, in a vexR-dependent manner, in response to the loss of RND efflux activity. This suggested that VexAB may function to export intracellular metabolites. Support for this hypothesis was provided by data showing that vexRAB was upregulated in several metabolic mutants including tryptophan biosynthetic mutants that were predicted to accumulate indole. In addition, vexRAB was found to be upregulated in response to exogenous indole and to contribute to indole resistance. The collective results indicate that vexR is required for vexRAB expression in response to VexAB substrates and that the VexAB RND efflux system modulates the intracellular levels of metabolites that could otherwise accumulate to toxic levels.
Highlights
Vibrio cholerae is a noninvasive gram negative bacterial pathogen that causes the disease cholera
This conclusion was supported by subsequent experiments showing that VexR directly bound the vexRAB promoter (Fig. 3C), that VexR was able to increase vexRAB expression in E. coli (Fig. 3B), and that vexR overexpression in V. cholerae resulted in a vexB-dependent growth advantage in the presence of sub-lethal concentrations of deoxycholate (Fig. 4)
V. cholerae lacks the Mar operon, VexR could function in a similar role as the Mar operon by contributing to vexRAB expression in response to antimicrobial exposure
Summary
Vibrio cholerae is a noninvasive gram negative bacterial pathogen that causes the disease cholera. Cholera is a severe acute diarrheal disease that affects an estimated 3–5 million people per year [1]. Untreated cholera can rapidly lead to dehydration, hypotensive shock, and death. Cholera is contracted by ingesting V. cholerae contaminated food or water [2]. V. cholerae colonizes the small intestine via a process that is dependent upon the PLOS ONE | DOI:10.1371/journal.pone.0117890. V. cholerae colonizes the small intestine via a process that is dependent upon the PLOS ONE | DOI:10.1371/journal.pone.0117890 February 19, 2015
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