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Acidic Microenvironment Determines Antibiotic Susceptibility and Biofilm Formation of Pseudomonas aeruginosa

Lin, Qiao (2022) Acidic Microenvironment Determines Antibiotic Susceptibility and Biofilm Formation of Pseudomonas aeruginosa. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Pseudomonas aeruginosa (P. aeruginosa) can chronically colonize in immunocompromised hosts, especially in cystic fibrosis (CF) lungs, where P. aeruginosa persists for decades and frequently exists as biofilms. The impaired function of cystic fibrosis transmembrane conductance regulator (CFTR) leads to abnormal epithelial Cl- /HCO3- transport and acidification of airway surface liquid. It has been reported that the CF lung microenvironment may be more acidic than those in non-CF due to the underlying problems of dysfunctional CFTR and the acidifying extracellular DNA originated from dead bacteria or host immune cells. However, it remains unclear why P. aeruginosa versus other pathogens most commonly infects the CF lung. We carried out studies to investigate if lower pH helps P. aeruginosa adapt and thrive in the CF-like acidic lung environment in the short term. We also presented evidence that the acidic biofilm lifestyle is selective for P. aeruginosa vfr mutations during long-term bacterial evolution studies, which had been identified in human CF respiratory longitudinal studies.
Our results revealed that, during adaptation to the environment, P. aeruginosa generally forms more biofilm and generates antibiotic resistance more quickly in acidic conditions. These adverse effects can be reversed by returning the acidic environment to physiologically neutral conditions. Our data provide mechanistic evidence linking the CF-specific acidic microenvironment to the reported emergence of P. aeruginosa vfr mutations in clinical CF isolates during long-term evolution.
P. aeruginosa appears to be highly adaptive to the CF-like acidic pH environment. By studying the effects of an acidic environment on bacterial response, we may provide a new therapeutic option in preventing chronic Pseudomonas aeruginosa infection and colonization. Specifically, targeting vfr may offer a new therapeutic option to eliminate bacterial biofilm formation, the main culprit contributing to the chronic P. aeruginosa colonization in CF.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lin, Qiaoqil29@pitt.eduQIL290000-0002-7017-8483
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLeikauf, Georgegleikauf@pitt.edugleikauf
Thesis AdvisorDi, Yuanpupeterdi@pitt.edupeterdi
Committee MemberDeslouches, Berthonytdesl19@pitt.edutdesl19
Committee MemberCooper, Vaughnvaughn.cooper@pitt.eduvaughn.cooper
Date: 4 January 2022
Date Type: Publication
Defense Date: 26 October 2021
Approval Date: 4 January 2022
Submission Date: 13 November 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 98
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: CF - Cystic Fibrosis, acidic pH, pseudomonas aeruginosa, biofilm, evolution, WGS, antibiotic resistance
Date Deposited: 04 Jan 2022 15:20
Last Modified: 04 Jan 2022 15:20
URI: http://d-scholarship.pitt.edu/id/eprint/41946

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