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Characterization of the links between RND family multidrug efflux systems and adaptive responses in Vibrio cholerae

Kunkle, Dillon (2020) Characterization of the links between RND family multidrug efflux systems and adaptive responses in Vibrio cholerae. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The Gram-negative bacterium Vibrio cholerae is the causative agent of the diarrheal disease cholera. V. cholerae is a natural inhabitant of marine ecosystems and causes infection following the consumption of V. cholerae contaminated food or water. Therefore, the lifestyle of pathogenic V. cholerae requires rapid transitions between aquatic ecosystems and colonization of the human gastrointestinal tract. These transitions are marked by swift and dramatic changes in environmental conditions including fluctuations in temperature, pH, salinity, oxygen tension, and the presence of antimicrobial compounds. For successful transitions between these disparate environments. V. cholerae must be able to sense and adapt to environmental fluctuations, this is achieved through the use of adaptive responses such as the induction of antimicrobial resistance mechanisms. Multidrug efflux pumps belonging to the RND superfamily contribute to adaptive resistance to a broad range of antimicrobial compounds including antibiotics, immune effectors, and detergents. Interestingly, RND-mediated efflux has also been linked to bacterial adaptive responses outside of antimicrobial resistance, suggesting RND efflux pumps perform native functions in bacterial physiology. Consistent with this, work from out laboratory has linked V. cholerae RND-mediated efflux to virulence factor production, metabolism, and stress responses. Yet, how RND-mediated efflux contributes to these adaptive responses remains mostly unknown. In the work presented in this dissertation we sought to explore the mechanistic links between V. cholerae RND efflux pumps and adaptive responses, and to exploit these links to identify novel signals and regulatory networks that participate in adaptive responses important for the V. cholerae life cycle. We found that the RND efflux pumps participate in iron acquisition, maintenance of membrane integrity, and metabolism through the secretion of vibriobactin. Further, we linked RND efflux to virulence factor production through the regulation of ompR expression. We defined the role of OmpR in V. cholerae biology, and found that it responds to components of bile and environmental pH, and contributes to the alkaline pH response. Collectively, this work illustrates some of the native function of V. cholerae RND efflux pumps, and indicates that they contribute to bacterial adaptive responses through the modulation of the intracellular concentration of signaling molecules.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kunkle, Dillondik35@pitt.edudik350000-0001-7579-4165
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorBina, Jamesjbina@pitt.edujbina
Committee MemberMcClane, Brucebamcc@pitt.edubamcc
Committee MemberShanks, Robertshanksrm@upmc.edushanksrm
Committee MemberThibodeau, PHthibodea@pitt.eduthibodea
Committee MemberRichardson, Anthonyricharar@pitt.eduricharar
Date: 9 August 2020
Date Type: Publication
Defense Date: 24 April 2020
Approval Date: 9 August 2020
Submission Date: 1 May 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 169
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: V. cholerae Cholera RND efflux Antibiotic resistance Two-component systems
Related URLs:
Date Deposited: 09 Aug 2020 19:53
Last Modified: 09 Aug 2022 05:15

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