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<p>Co-amoxiclav (amoxicillin and clavulanate) is a commonly used combination antibiotic, with resistance in <i>Escherichia coli</i> associated with increased mortality. The class A beta-lactamase <i>bla</i><sub>TEM-1</sub> is often carried by resistant <i>E. coli</i> but exhibits high phenotypic heterogeneity, complicating genotype-phenotype predictions. We curated a dataset of <i>n</i> = 377 diverse <i>E. coli</i> isolates where the only acquired beta-lactamase was <i>bla</i><sub>TEM-1</sub>. We generated hybrid assemblies and co-amoxiclav minimum inhibitory concentrations (MICs), and <i>bla</i><sub>TEM-1</sub> qPCR expression data for a subset (<i>n</i> = 67/377). We first tested whether intrinsic expression of <i>bla</i><sub>TEM-1</sub> varied between <i>E. coli</i> lineages, for example, from regulatory system differences, which are challenging to genomically quantify. Using genotypic features, we built a hierarchical Bayesian model for <i>bla</i><sub>TEM-1</sub> expression, controlling for phylogeny. Expression varied across the phylogeny, with some lineages (phylogroups B1 and C, ST12) expressing <i>bla</i><sub>TEM-1</sub> more than others (phylogroups E and F, ST372). Next, we built a second model to predict isolate MIC from genotypic features, again controlling for phylogeny. Phylogeny alone shifted MIC past the clinical breakpoint in 19% (55/292) of isolates with greater-than-chance probability, mostly representing ST12, ST69 and ST127. A third causal model confirmed that phylogenetic influence on <i>bla</i><sub>TEM-1</sub> expression drove variation in MIC. We speculate that intergenic variation underlies this effect.</p>

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Escherichia coli phylogeny drives co-amoxiclav resistance through variable expression of TEM-1 beta-lactamase

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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  • William Matlock,
  • Gillian Rodger,
  • Emma Pritchard,
  • Matthew Colpus,
  • Natalia Kapel,
  • Lucinda Barrett,
  • Marcus Morgan,
  • Sarah Oakley,
  • Katie L. Hopkins,
  • Aysha Roohi,
  • Drosos Karageorgopoulos,
  • Matthew B. Avison,
  • A. Sarah Walker,
  • Samuel Lipworth,
  • Nicole Stoesser

摘要

Co-amoxiclav (amoxicillin and clavulanate) is a commonly used combination antibiotic, with resistance in Escherichia coli associated with increased mortality. The class A beta-lactamase blaTEM-1 is often carried by resistant E. coli but exhibits high phenotypic heterogeneity, complicating genotype-phenotype predictions. We curated a dataset of n = 377 diverse E. coli isolates where the only acquired beta-lactamase was blaTEM-1. We generated hybrid assemblies and co-amoxiclav minimum inhibitory concentrations (MICs), and blaTEM-1 qPCR expression data for a subset (n = 67/377). We first tested whether intrinsic expression of blaTEM-1 varied between E. coli lineages, for example, from regulatory system differences, which are challenging to genomically quantify. Using genotypic features, we built a hierarchical Bayesian model for blaTEM-1 expression, controlling for phylogeny. Expression varied across the phylogeny, with some lineages (phylogroups B1 and C, ST12) expressing blaTEM-1 more than others (phylogroups E and F, ST372). Next, we built a second model to predict isolate MIC from genotypic features, again controlling for phylogeny. Phylogeny alone shifted MIC past the clinical breakpoint in 19% (55/292) of isolates with greater-than-chance probability, mostly representing ST12, ST69 and ST127. A third causal model confirmed that phylogenetic influence on blaTEM-1 expression drove variation in MIC. We speculate that intergenic variation underlies this effect.