Heteroresistance in Enterobacter cloacae complex caused by variation in transient gene amplification events
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 bla<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.
Authors
- Dennis Hanke (ORCID: https://orcid.org/0000-0002-3594-4234)
- Niclas Nordholt (ORCID: https://orcid.org/0000-0001-5788-0801)
- Fereshteh Ghazisaeedi
- Silver Anthony Wolf (ORCID: https://orcid.org/0009-0004-8164-7216)
- Johannes Kupke (ORCID: https://orcid.org/0000-0001-9045-9410)
- Ulrich K. Steiner (ORCID: https://orcid.org/0000-0002-1778-5989)
- Antina Lübke‐Becker
- Yuwen Fang (ORCID: https://orcid.org/0000-0001-9640-6336)
- Torsten Semmler (ORCID: https://orcid.org/0000-0002-2225-7267)
- Marcus Fulde (ORCID: https://orcid.org/0000-0003-0469-3951)
- Julian Brombach
- Karsten Tedin (ORCID: https://orcid.org/0000-0003-2109-0730)
- Stefanie Schreiber (ORCID: https://orcid.org/0000-0003-4439-4374)
- Benno Kuropka (ORCID: https://orcid.org/0000-0001-5088-6346)
- Lakshmipriya Thrukonda
Institutions
- Federal Institute For Materials Research and Testing (DE)
- Robert Koch Institute (DE)
- Freie Universität Berlin (DE)
Publication Details
- Journal
- npj Antimicrobials and Resistance
- Published
- 2025-02-22
- DOI
- https://doi.org/10.1038/s44259-025-00082-7
- Citations
- 5
- Primary Topic
- Antibiotic Resistance in Bacteria
- Type
- article
- Field-Weighted Citation Impact
- 2.36
Funders
- Deutsche Forschungsgemeinschaft
- Freie Universität Berlin
- H. Wilhelm Schaumann Stiftung