Exploring Bacterial Tolerance: A Hidden Culprit in Treatment Failure of Urinary Tract Infections Restricted; Files Only

Abstract

 Antibiotic resistance poses an alarming threat to global health, with antibiotic tolerance and heteroresistance complicating the efficacy of therapeutic interventions. This study goes into the underestimated dimension of bacterial drug tolerance—defined as the ability of bacterial populations to endure prolonged exposure to bactericidal antibiotics—and its role in fostering heteroresistance, where bacterial subpopulations within the same colony display differential resistance levels. [1]

  Utilizing Time Kill Assays (TKAs) on over 300 Urinary Tract Infection (UTI) patient samples, we identified a significant correlation between treatment failure and the presence of the tolerance phenotype. This underscored the detrimental impact of tolerance on therapeutic efficacy. Furthermore, resistance escalation observed in a Tazobactam and Piperacillin-containing medium after 24 hours, and its subsequent reversion in drug-free media for several strains, highlighted the dynamic nature of bacterial resistance. Serial passages over two weeks on plates with varying drug concentrations provided insights into the sustainability of resistance escalation and its strong correlation with treatment outcomes.

  Critical to unraveling the genetic underpinnings of these observations, whole genome sequencing followed by quantitative PCR (qPCR) on selected strains revealed amplification in several antibiotic-related genetic areas, including blaTEM-1 and chrA. These findings suggest a potential genetic mechanism behind the observed treatment failures and underscore the complex interplay between genetic evolution and antibiotic exposure.

  Our comprehensive analysis not only reaffirms the pivotal role of bacterial drug tolerance in treatment regimen failures but also emphasizes the urgent need for clinical drug testing protocols to account for tolerance mechanisms and heteroresistance. By integrating molecular genetics with clinical data, this study paves the way for understanding the genetic mechanisms behind antibiotic resistance and tolerance, marking a significant stride towards addressing this global public health challenge.

Table of Contents

Introduction                                                                                                                                     1

Materials and Methods                                                                                                                    6

Results                                                                                                                                             8

Discussion                                                                                                                                      15

References                                                                                                                                      17

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Molecular Biology, Microbiology Biology, Genetics
Keyword	antibioitc resistance genetic amplification Microbiology anbiotic tolerance
Committee Chair / Thesis Advisor	David S. Weiss, Emory University
Committee Members	Anita H. Corbett, Emory University Berman J. Gordon, Emory University

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