Abnormal immunological profile and vaginal microbiota in women prone to urinary tract infections

Authors

Lee W. Goneau, The University of Western Ontario
Nigel S. Yeoh, University of Otago
Kyle W. MacDonald, The University of Western Ontario
Peter A. Cadieux, The University of Western Ontario
Jeremy P. Burton, The University of Western Ontario
Hassan Razvi, The University of Western Ontario
Gregor Reid, The University of Western Ontario

Document Type

Article

Publication Date

1-1-2014

Journal

Antimicrobial Agents and Chemotherapy

Volume

58

Issue

4

First Page

2089

Last Page

2097

URL with Digital Object Identifier

10.1128/AAC.02552-13

Abstract

Persister cells represent a multidrug-tolerant (MDT), physiologically distinct subpopulation of bacteria. The ability of these organisms to survive lethal antibiotic doses raises concern over their potential role in chronic disease, such as recurrent urinary tract infection (RUTI). Persistence is believed to be conveyed through global metabolic dormancy, which yields organisms unresponsive to external stimuli. However, recent studies have contested this stance. Here, various antibiotics that target different cellular processes were used to dissect the activity of transcription, translation, and peptidoglycan turnover in persister cells. Differential susceptibility patterns were found in type I and type II persisters, and responses differed between Staphylococcus saprophyticus and Escherichia coli uropathogens. Further, SOS-deficient strains were sensitized to ciprofloxacin, suggesting DNA gyrase activity in persisters and indicating the importance of active DNA repair systems for ciprofloxacin tolerance. These results indicate that global dormancy per se cannot sufficiently account for antibiotic tolerance. Rather, the activity of individual cellular processes dictates multidrug tolerance in an antibiotic-specific fashion. Furthermore, the susceptibility patterns of persisters depended on their mechanisms of onset, with subinhibitory antibiotic pretreatments selectively shutting down cognate targets and increasing the persister fraction against the same agent. Interestingly, antibiotics targeting transcription and translation enhanced persistence against multiple agents indirectly related to these processes. Conducting these assays with uropathogenic E. coli isolated from RUTI patients revealed an enriched persister fraction compared to organisms cleared with standard antibiotic therapy. This finding suggests that persister traits are either selected for during prolonged antibiotic treatment or initially contribute to therapy failure. Copyright © 2014, American Society for Microbiology. All Rights Reserved.