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

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 and Nicole Stoesser ()
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William Matlock: University of Oxford
Gillian Rodger: University of Oxford
Emma Pritchard: University of Oxford
Matthew Colpus: The National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford
Natalia Kapel: The National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford
Lucinda Barrett: Oxford University Hospitals NHS Foundation Trust
Marcus Morgan: Oxford University Hospitals NHS Foundation Trust
Sarah Oakley: Oxford University Hospitals NHS Foundation Trust
Katie L. Hopkins: UK Health Security Agency
Aysha Roohi: University of Oxford
Drosos Karageorgopoulos: Oxford University Hospitals NHS Foundation Trust
Matthew B. Avison: University of Bristol
A. Sarah Walker: University of Oxford
Samuel Lipworth: University of Oxford
Nicole Stoesser: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63714-6

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