In vitro selection of cefiderocol-resistant mutants in Acinetobacter baumannii harbouring the most common carbapenemase genes
DOKPE
- Raro, Otávio Hallal Ferreira ORCID University of Fribourg
- Findlay, Jacqueline ORCID University of Fribourg
- Poirel, Laurent ORCID University of Fribourg
- Decousser, Jean-Winoc ORCID University Hospital Henri Mondor, France
- Nordmann, Patrice ORCID University of Fribourg
- 2025
Published in:
- Journal of Antimicrobial Chemotherapy. - Oxford Academic. - 2025
English
Background
Carbapenem-resistant Acinetobacter baumannii (CRAB) represents a critical global health threat due to its high mortality rates in infections, limited treatment options and resistance to last-resort antibiotics. Cefiderocol, a novel siderophore-conjugated cephalosporin, has emerged as a promising therapeutic agent against such infections. However, resistance to this antibiotic has already been reported.
Objectives
To investigate whether the production of common carbapenemases affects cefiderocol susceptibility in A. baumannii and to identify the genetic mechanisms underlying resistance development.
Methods
Using isogenic A. baumannii CIP 7010 strains carrying carbapenemase genes commonly identified in that species, namely blaNDM-1, blaOXA-23, blaOXA-40 or blaOXA-58, mutants were selected under increasing cefiderocol pressure. Mutants obtained were subjected to MIC determinations, WGS, complementation assays, real-time quantitative PCR (RT-qPCR) and fitness assays.
Results
WGS of cefiderocol-resistant isolates revealed recurrent mutations in genes encoding the global regulators BfmS and OxyR, rather than in genes directly related to iron uptake, PBPs or β-lactamases. Complementation assays with WT bfmRS or oxyR resulted in a reversion to the parental strain cefiderocol MICs. RT-qPCR indicated that these global regulators reduced expression of piuA and pirA genes involved in iron uptake, and hence were associated with a previously unknown mechanism that results in resistance to cefiderocol.
Conclusions
Global regulators BfmS and OxyR were responsible for decreasing the expression of piuA and pirA genes, thereby contributing to cefiderocol resistance. This evolutionary analysis enhances our understanding of the mechanisms underlying cefiderocol resistance and identifies potential molecular targets for the development of new therapeutics against CRAB.
Carbapenem-resistant Acinetobacter baumannii (CRAB) represents a critical global health threat due to its high mortality rates in infections, limited treatment options and resistance to last-resort antibiotics. Cefiderocol, a novel siderophore-conjugated cephalosporin, has emerged as a promising therapeutic agent against such infections. However, resistance to this antibiotic has already been reported.
Objectives
To investigate whether the production of common carbapenemases affects cefiderocol susceptibility in A. baumannii and to identify the genetic mechanisms underlying resistance development.
Methods
Using isogenic A. baumannii CIP 7010 strains carrying carbapenemase genes commonly identified in that species, namely blaNDM-1, blaOXA-23, blaOXA-40 or blaOXA-58, mutants were selected under increasing cefiderocol pressure. Mutants obtained were subjected to MIC determinations, WGS, complementation assays, real-time quantitative PCR (RT-qPCR) and fitness assays.
Results
WGS of cefiderocol-resistant isolates revealed recurrent mutations in genes encoding the global regulators BfmS and OxyR, rather than in genes directly related to iron uptake, PBPs or β-lactamases. Complementation assays with WT bfmRS or oxyR resulted in a reversion to the parental strain cefiderocol MICs. RT-qPCR indicated that these global regulators reduced expression of piuA and pirA genes involved in iron uptake, and hence were associated with a previously unknown mechanism that results in resistance to cefiderocol.
Conclusions
Global regulators BfmS and OxyR were responsible for decreasing the expression of piuA and pirA genes, thereby contributing to cefiderocol resistance. This evolutionary analysis enhances our understanding of the mechanisms underlying cefiderocol resistance and identifies potential molecular targets for the development of new therapeutics against CRAB.
- Faculty
- Faculté des sciences et de médecine
- Department
- Section de médecine
- Language
-
- English
- Classification
- Pathology, clinical medicine
- Other electronic version
- License
-
CC BY
- Open access status
- gold
- Identifiers
- Persistent URL
- https://folia.unifr.ch/unifr/documents/334013
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