Language
English
Publication Date
7-1-2025
Journal
Nature Communications
DOI
10.1038/s41467-025-60828-9
PMID
40593643
PMCID
PMC12216759
PubMedCentral® Posted Date
7-1-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Our understanding of the rapid adaptation of bacteria to resist novel drugs is growing beyond known mechanisms such as mobile genetic elements and mutation selection. Heteroresistance (HR) is a form of antibiotic resistance where a phenotypically unstable minority resistant subpopulation co-exists with a susceptible population. We sought to uncover the mechanism of heteroresistance to cefiderocol, a novel β-lactam developed to resist β-lactamases including extended-spectrum-β-lactamases (ESBLs), which has been recently reported but poorly understood. We observe HR to cefiderocol among clinical isolates collected before its use. The resistant subpopulation in Enterobacter is a continuum; increasing copy number of a gene encoding an ESBL ineffective against cefiderocol mediates increased resistance in decreasing numbers of cells. We then pursued the factors that control the magnitude of amplification. We observe that ESBL activity correlates with the level of amplification, and thus that increased copy number can compensate for poor enzymatic activity. A Klebsiella isolate from a clinical treatment failure also demonstrates amplification, highlighting the potential relevance of this β-lactamase gene amplification-mediated HR. These data provide insights into factors controlling dynamics of HR and how bacteria can use gene amplification to flexibly confront new antibiotic threats.
Keywords
beta-Lactamases, Anti-Bacterial Agents, Microbial Sensitivity Tests, Humans, beta-Lactams, Cephalosporins, DNA Copy Number Variations, Gene Dosage, beta-Lactam Resistance, Enterobacter, Klebsiella
Published Open-Access
yes
Recommended Citation
Choby, Jacob E; Ozturk, Tugba; Abbott, Carter N; et al., "Copy Number Flexibility Facilitates Heteroresistance to Increasing Antibiotic Pressure and Threatens the Beta-Lactam Pipeline" (2025). Faculty, Staff and Students Publications. 6549.
https://digitalcommons.library.tmc.edu/baylor_docs/6549