Articlenpj antimicrobials and resistance2026
Population size modulates the transition from gene amplification-mediated heteroresistance to stable resistance.
Article in npj antimicrobials and resistance, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Heteroresistance is characterized by antibiotic-resistant subpopulations which can be underpinned by reversible gene duplication-amplification (GDA) of antibiotic resistance genes. It is often considered a precursor of stable resistance mutations. We investigated the evolutionary dynamics between GDA-mediated heteroresistance and stable resistance mutations in a clinical Enterobacter cloacae complex isolate. Exposure to ceftazidime resulted in enrichment of ampC β-lactamase GDAs in a concentration-dependent manner. Long-term exposure and high concentrations of ceftazidime selected for stable resistance mutations in dacB and ampD, a decrease of GDAs and a loss of population heterogeneity. Evolution experiments and mathematical modelling suggest that, in large populations, competition with GDA-carrying subpopulations can prolong fixation of stable resistance mutations in the population. By contrast, heteroresistance rescues small populations upon sudden antibiotic challenge, thereby acting as a precursor of stable resistance. This study highlights a previously underappreciated dual, population-size dependent role for GDAs in the transition from heteroresistance to stable resistance.
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