An investigation of gene dosage reveals that increased sensitivity to D-cycloserine divergently impacts the transience of heteroresistance in Escherichia coli
Abstract
Heteroresistance describes the phenomenon where seemingly isogenic bacterial populations contain subpopulations with elevated resistance compared to the susceptible majority that are often missed in routine susceptibility testing. The enhanced resistance of those subpopulations can either be maintained (stable) or quickly lost (unstable/transient) after treatment, where transient cases return susceptibility results identical to those of original cultures. Recent work has implicated increased gene dosage of resistance determinants as a major cause of unstable heteroresistance in clinical isolates. Inspired by that work, we sought to systematically evaluate how gene dosage of an antibiotic's target network components impacted heteroresistance and its stability. To accomplish that, we used Escherichia coli MG1655 as a model organism, and D-cycloserine (DCS), a cell-wall synthesis inhibitor that enters through a transporter (CycA) and inhibits multiple enzymes (DdlA, DdlB, DadX, and Alr), as a model antibiotic. To measure heteroresistance, we used population analysis profiling, and to quantify stability, we used a population-level model to define a heteroresistance stability index ([Formula: see text]), which quantifies the proportion of heteroresistant subpopulation j that maintained elevated resistance over t generations. We found that increased sensitivity to DCS through gene dosage variation of cycA and ddlB divergently impacted heteroresistance stability, with ddlB…
Read the paper
Related studies
- Horizontal gene transfer in the human gastrointestinal tract: potential spread of antibiotic resistance genes
- Mutation supply and relative fitness shape the genotypes of ciprofloxacin-resistant Escherichia coli
- Genomic Survey of E. coli From the Bladders of Women With and Without Lower Urinary Tract Symptoms
- Characterization of cefotaxime-resistant urinary Escherichia coli from primary care in South-West England 2017–18
- Fitness cost constrains the spectrum of marR mutations in ciprofloxacin-resistant Escherichia coli
- Emerging evidence-based innovative approaches to control catheter-associated urinary tract infection: a review
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.