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.
| Original language | English |
|---|---|
| Journal | Nature Communications |
| Early online date | 30 Sept 2025 |
| DOIs | |
| Publication status | Published - 30 Sept 2025 |
| Externally published | Yes |
Data Availability Statement
Metadata for all n = 377 genomes included in the final analysis is given in Supplementary Data File 1. Metadata for all n = 451 blaTEM-1 annotations identified in these genomes is given in Supplementary Data File 2. qPCR expression data for all replicates is given in Supplementary Data File 3. NCBI accessions for short- and long-read sets and assemblies are given in Supplementary Data File 4. All Supplementary Data Files are also stably archived at https://doi.org/10.5281/zenodo.16731807.Funding
This work was funded by the National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance (NIHR200915), a partnership between the UK Health Security Agency (UKHSA) and the University of Oxford. It was also supported by the NIHR Oxford Biomedical Research Centre (BRC). The computational aspects of this research were funded from the NIHR Oxford BRC with additional support from the Wellcome Trust Core Award Grant Number 203141/Z/16/Z. The views expressed are those of the author(s) and not necessarily those of the NIHR, UKHSA or the Department of Health and Social Care. The authors thank Jarrod Hadfield for providing guidance on implementing the MCMCglmm library.