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<p>Heteroresistance (HR) in bacteria describes a subpopulational phenomenon of antibiotic resistant cells of a generally susceptible population. Here, we investigated the molecular mechanisms and phenotypic characteristics underlying HR to ceftazidime (CAZ) in a clinical <i>Enterobacter cloacae</i> complex strain (ECC). We identified a plasmid-borne gene duplication-amplification (GDA) event of a region harbouring an <i>ampC</i> gene encoding a β-lactamase <i>bla</i><sub>DHA-1</sub> as the key determinant of HR. Individual colonies exhibited variations in the copy number of the genes resulting in resistance level variation which correlated with growth onset (lag times) and growth rates in the presence of CAZ. GDA copy number heterogeneity occurred within single resistant colonies, demonstrating heterogeneity of GDA on the single-cell level. The interdependence between GDA, lag time and antibiotic treatment and the strong plasticity underlying HR underlines the high risk for misdetection of antimicrobial HR and subsequent treatment failure.</p>

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Heteroresistance in Enterobacter cloacae complex caused by variation in transient gene amplification events

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月22日

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  • Johannes Kupke,
  • Julian Brombach,
  • Yuwen Fang,
  • Silver A. Wolf,
  • Lakshmipriya Thrukonda,
  • Fereshteh Ghazisaeedi,
  • Benno Kuropka,
  • Dennis Hanke,
  • Torsten Semmler,
  • Niclas Nordholt,
  • Frank Schreiber,
  • Karsten Tedin,
  • Antina Lübke-Becker,
  • Ulrich K. Steiner,
  • Marcus Fulde

摘要

Heteroresistance (HR) in bacteria describes a subpopulational phenomenon of antibiotic resistant cells of a generally susceptible population. Here, we investigated the molecular mechanisms and phenotypic characteristics underlying HR to ceftazidime (CAZ) in a clinical Enterobacter cloacae complex strain (ECC). We identified a plasmid-borne gene duplication-amplification (GDA) event of a region harbouring an ampC gene encoding a β-lactamase blaDHA-1 as the key determinant of HR. Individual colonies exhibited variations in the copy number of the genes resulting in resistance level variation which correlated with growth onset (lag times) and growth rates in the presence of CAZ. GDA copy number heterogeneity occurred within single resistant colonies, demonstrating heterogeneity of GDA on the single-cell level. The interdependence between GDA, lag time and antibiotic treatment and the strong plasticity underlying HR underlines the high risk for misdetection of antimicrobial HR and subsequent treatment failure.