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Updated: Jun 20, 2025
Mutagenesis and Functional Selection Protocols for Directed Evolution of Proteins in E. coli
Published on: March 16, 2011
The effect of antibiotic selection on collateral effects and evolvability of uropathogenic Escherichia coli
Beth James1, Hishikha Reesaul1, Sidra Kashif1
1Department of Biosciences, Nottingham Trent University, Clifton Campus, College Drive, Clifton, Nottingham NG11 8NS UK.
Abstract:
Trimethoprim is recommended as a first-line treatment of urinary tract infections (UTIs) in the UK. In 2018, 31.4% of Escherichia coli isolated from UTIs in England were trimethoprim-resistant, leading to overreliance on other first and second-line antibiotics. Here, we assessed whether, in principle, prior selection with trimethoprim results in collateral effects to other antibiotics recommended for the treatment of UTIs. As collateral effects, we considered changes in susceptibility, mutation-selection window and population establishment probability. We selected 10 trimethoprim-resistant derivatives from three clinical isolates of uropathogenic Escherichia coli. We found that mutations conferring trimethoprim resistance did not have any collateral effects on fosfomycin. In contrast, resistance to trimethoprim resulted in decreased susceptibility (collateral resistance) to nitrofurantoin, below the clinical breakpoint and narrowed the mutation-selection window, thereby reducing the maximum concentration for selection of nitrofurantoin resistance mutations. Our analyses demonstrate that multiple collateral responses should be accounted for when predicting and optimising antibiotic use, limiting future antimicrobial resistance emergence.
Insights
Trimethoprim resistance in urinary tract infections may cause collateral resistance to other antibiotics like nitrofurantoin. This finding is crucial for optimizing antibiotic use and limiting antimicrobial resistance.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Trimethoprim is a first-line antibiotic for urinary tract infections (UTIs) in the UK.
- High rates of trimethoprim-resistant *Escherichia coli* (31.4% in 2018) necessitate understanding antibiotic collateral effects.
Purpose of the Study:
- To investigate if trimethoprim resistance confers collateral effects on other UTI antibiotics.
- To assess impacts on antibiotic susceptibility, mutation-selection window, and population establishment.
Main Methods:
- Generated 10 trimethoprim-resistant *Escherichia coli* derivatives from three clinical isolates.
- Evaluated changes in susceptibility and mutation-selection dynamics for fosfomycin and nitrofurantoin.
Main Results:
- Trimethoprim resistance mutations showed no collateral effects on fosfomycin susceptibility.
- Resistance to trimethoprim led to collateral resistance to nitrofurantoin, falling below clinical breakpoints.
- The mutation-selection window for nitrofurantoin resistance was narrowed.
Conclusions:
- Prior trimethoprim selection can lead to collateral resistance, impacting nitrofurantoin efficacy.
- Considering multiple collateral responses is vital for predicting antibiotic effectiveness and curbing antimicrobial resistance.
- This research informs strategies for optimizing antibiotic therapy and mitigating resistance.
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