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Characterization of the Vibrio cholerae RND efflux systems

Taylor, Dawn L. (2014) Characterization of the Vibrio cholerae RND efflux systems. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The resistance-nodulation-division (RND) family efflux systems are ubiquitous transporters that have been extensively studied due to their ability to efflux a broad range of xenobiotic substrates. There is increasing evidence to suggest that the RND efflux systems have physiological roles beyond xenobiotic resistance to include pathogenesis and cellular stress responses. The Vibrio cholerae genome encoded six RND efflux systems: VexAB, VexCD, VexEF, VexGH, VexIJK, and VexLM. This work sought to characterize the role of these systems in antimicrobial resistance, pathogenesis, and environmental stress.
The V. cholerae RND efflux systems were characterized according to their substrate specificity and contribution to antimicrobial resistance. The VexAB, VexCD, VexGH, and VexIJK RND efflux systems were shown to contribute to resistance against multiple antibiotics, bile salts, and other detergents. In addition to functioning in antimicrobial resistance, the RND efflux systems were found to function in the extrusion of metabolic intermediates. In the absence of RND efflux, the accumulation of potentially toxic metabolites induced the expression of vexRAB, vexGH, and the Cpx membrane stress response system. Subsequent studies showed that independent activation of the Cpx system also resulted in the induction of vexRAB and vexGH expression, which indicated that the Cpx system and the vexRAB and vexGH RND efflux systems were reciprocally regulated. Collectively these results suggested a model whereby the vexRAB and vexGH RND efflux systems function to reduce cellular stress resulting from endogenous metabolites, xenobiotics, and factors that induce a membrane stress response.
The VexAB RND system was also found to be positively regulated by VexR, a TetR-family regulator that was encoded within the same operon (i.e. vexRAB). VexR activated vexRAB expression in response to VexAB efflux substrates and in the absence of RND efflux activity. The latter phenotype suggested that the VexR modulated vexRAB expression in response to endogenous cues. Overall the data presented in this thesis supported the conclusion that the V. cholerae RND efflux systems functioned in responses that were essential for environmental adaptation including intestinal colonization, xenobiotic resistance, metabolic imbalance, and membrane stress.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Taylor, Dawn L.dlt31@pitt.eduDLT31
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorBina, James E.jbina@pitt.eduJBINA
Committee MemberBomberger, Jennifer M.jbomb@pitt.eduJBOMB
Committee MemberLiu, Xinyuxinyuliu@pitt.eduXINYULIU
Committee MemberMcClane, Bruce A.bamcc@pitt.eduBAMCC
Committee MemberShanks, Robert M. Q. shanksrm@upmc.edu
Date: 20 August 2014
Date Type: Publication
Defense Date: 8 August 2014
Approval Date: 20 August 2014
Submission Date: 20 August 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 181
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Vibrio cholerae, RND efflux systems, TetR regulator, Cpx system, indole, cholera toxin
Date Deposited: 20 Aug 2014 15:44
Last Modified: 15 Nov 2016 14:23
URI: http://d-scholarship.pitt.edu/id/eprint/22786

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