title: Escherichia coli mutators present an enhanced risk for emergence of antibiotic resistance during urinary tract infections.
abstract: Mutators may present an enhanced risk for the emergence of antibiotic resistance in bacteria during chemotherapy. Using Escherichia coli mutators as a model, we evaluated their ability to develop resistance to antibiotics routinely used for the treatment of urinary tract infections (UTIs). Under conditions that simulate therapeutic drug concentrations in humans, low-level resistance to trimethoprim, gentamicin, and cefotaxime emerged more frequently in mutators than normal strains. Resistance to trimethoprim in both cell types arose from a single point mutation in folA (Ile94-->Leu) and cefotaxime resistance resulted from loss of outer membrane porin OmpF. The mechanisms of gentamicin resistance could not be defined, but resistance did not result from mutations in ribosomal protein L6 (rplF). Although similar mechanisms of low-level antibiotic resistance probably arise in these strains, mutators are a risk factor because the increased generation of mutants with low-level resistance enhances the opportunity for subsequent emergence of high-level resistance.
authors.affiliation: Antimicrobial Research Centre and Division of Microbiology, School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Keith
authors.initials: K
authors.lastname: Miller
authors.forename: Alexander John
authors.initials: AJ
authors.lastname: O'Neill
authors.forename: Ian
authors.initials: I
authors.lastname: Chopra
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics; D001426:Bacterial Proteins / Q000032:analysis / Q000096:biosynthesis; D003470:Culture Media; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics*; D004927:Escherichia coli Infections / Q000382:microbiology*; D004996:Ethidium / Q000378:metabolism; D005470:Fluorometry; D005787:Gene Frequency; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000302:isolation & purification; D014552:Urinary Tract Infections / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D003470:Culture Media; D013762:Tetrahydrofolate Dehydrogenase; D004996:Ethidium