ArticleNature communications2025
Copy number flexibility facilitates heteroresistance to increasing antibiotic pressure and threatens the beta-lactam pipeline.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Dual population-level processes contribute to polyclonal ceftiofur heteroresistance in swine-derivedVirulence · 2026Article
- Transcriptional regulation drives heteroresistance inmSystems · 2026Article
- Combinatorial action of regulatory systems generates colistin heteroresistance.Science advances · 2026Article
- Heterogeneity in the response to the metabolic environment drives fosfomycin heteroresistance.Nature communications · 2026Article
- Intrinsic resistance networks shape cefiderocol susceptibility in ST258Antimicrobial agents and chemotherapy · 2026Article
- Bacterial heteroresistance mechanisms, dynamics, and emerging diagnostic approaches.Bioscience reports · 2026Review
- Heterogeneity in microbial antibiotic responses: genetic basis and within-host evolution.Trends in genetics : TIG · 2026Review
- Suboptimal ceftazidime-avibactam exposure drives sequentialMicrobiology spectrum · 2026Article
- Novel Insights into Carbapenem Resistance: Mechanisms, Diagnostics, and Future Directions.Antibiotics (Basel, Switzerland) · 2026Review
- Resistance, heteroresistance, and fitness costs drive colistin treatment failure duringProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Cooperative antibiotic resistance in bacteria: beyond biofilms.Frontiers in microbiology · 2026Review
- Resistance, heteroresistance and fitness costs drive colistin treatment failure duringbioRxiv : the preprint server for biology · 2025Article
- The association between undetected heteroresistance and antibiotic treatment failure in complicated urinary tract infection.medRxiv : the preprint server for health sciences · 2025Article
- Antibiotic resistance mediated by gene amplifications.npj antimicrobials and resistance · 2024Review
Corrections and comments
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Authors and funding
9 authors.
Funding
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.
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