Beta-lactamase dependent and independent evolutionary paths to high-level ampicillin resistance

0301 basic medicine QA75 Electronic computers. Computer science / számítástechnika 570 0303 health sciences Whole Genome Sequencing számítógéptudomány Science Q 610 Microbial Sensitivity Tests Article beta-Lactamases Anti-Bacterial Agents Evolution, Molecular Bacterial Proteins Mutation Escherichia coli Ampicillin QH301 Biology / biológia Ampicillin Resistance
DOI: 10.1038/s41467-024-49621-2 Publication Date: 2024-06-25T17:03:01Z
ABSTRACT
AbstractThe incidence of beta-lactam resistance among clinical isolates is a major health concern. A key method to study the emergence of antibiotic resistance is adaptive laboratory evolution. However, in the case of the beta-lactam ampicillin, bacteria evolved in laboratory settings do not recapitulate clinical-like resistance levels, hindering efforts to identify major evolutionary paths and their dependency on genetic background. Here, we used the Microbial Evolution and Growth Arena (MEGA) plate to select ampicillin-resistant Escherichia coli mutants with varying degrees of resistance. Whole-genome sequencing of resistant isolates revealed that ampicillin resistance was acquired via a combination of single-point mutations and amplification of the gene encoding beta-lactamase AmpC. However, blocking AmpC-mediated resistance revealed latent adaptive pathways: strains deleted for ampC were able to adapt through combinations of changes in genes involved in multidrug resistance encoding efflux pumps, transcriptional regulators, and porins. Our results reveal that combinations of distinct genetic mutations, accessible at large population sizes, can drive high-level resistance to ampicillin even independently of beta-lactamases.
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