Cefiderocol resistance genes identified in environmental samples using functional metagenomics
Journal article, 2026
Antibiotic resistance poses a global public health threat, which can originate from the transfer of environmental antibiotic resistance genes to pathogenic bacteria, as highlighted by the "One Health" framework. Cefiderocol is a siderophore cephalosporin recently introduced in clinical practice which displays a "Trojan Horse" mechanism, utilizing bacterial iron transportation systems for cell entry. Although it is only used as a last-line antibiotic, resistance has already been observed in clinical isolates. Yet, cefiderocol resistance genes are difficult to monitor as resistance mechanisms remain mostly undescribed in antibiotic resistance gene databases and therefore uncharacterized in the environment. To address this critical gap, we applied functional metagenomics to diverse environmental samples (wastewater, freshwater, and soil) from France, Germany, Sweden, and Pakistan. Four antibiotic resistant genes were identified as responsible for increased cefiderocol minimum inhibitory concentrations to clinically-relevant levels (ranging from 1 to 4 mg/l), including ꞵ-lactamases (VEB-3, OXA-372 homolog, and YbxI homolog) and a partial penicillin-binding protein homolog. None of these genes had been previously reported as a cefiderocol resistance gene. Three out of four had their closest homologs in pathogenic bacteria. The blaVEB-3 gene was associated with a mobile genetic element and distributed across all wastewater metagenomes analyzed in this study. We therefore highlight the critical need for functional metagenomics, to characterize previously uncharacterized last-line antibiotic resistance mechanisms which will be used to enrich antibiotic resistance gene databases and thereby improving antibiotic resistance surveillance in all One Health compartments.
antibiotic resistance
functional metagenomics
cefiderocol
Author
Rémi Gschwind
Paris Descartes University
Mehdi Bonnet
Paris Descartes University
Assistance publique – Hôpitaux de Paris (AP-HP)
Anna Abramova
University of Gothenburg
Chalmers, Life Sciences, Systems and Synthetic Biology
Víctor Hugo Jarquín-Díaz
German Center for Cardiovascular Research DZHK
Helmholtz Association of German Research Centres
Charité University Medicine Berlin
Marcus Wenne
Chalmers, Life Sciences, Systems and Synthetic Biology
University of Gothenburg
Ulrike Löber
Helmholtz Association of German Research Centres
German Center for Cardiovascular Research DZHK
Charité University Medicine Berlin
Nicolas Godron
Paris Descartes University
Ioannis D. Kampouris
Technische Universität Dresden
Faina Tskhay
Technische Universität Dresden
Fouzia Nahid
Quaid-i-Azam University
Chloé Debroucker
Paris Descartes University
Maximilien Bui-Hai
Paris Descartes University
Inès El Aiba
Paris Descartes University
Uli Klümper
Technische Universität Dresden
Thomas U. Berendonk
Technische Universität Dresden
Sofia K. Forslund
Structural and Computational Biology Unit
German Center for Cardiovascular Research DZHK
Helmholtz Association of German Research Centres
Charité University Medicine Berlin
Rabaab Zahra
Quaid-i-Azam University
Johan Bengtsson Palme
Chalmers, Life Sciences, Systems and Synthetic Biology
University of Gothenburg
Etienne Ruppé
Paris Descartes University
Assistance publique – Hôpitaux de Paris (AP-HP)
ISME Journal
1751-7362 (ISSN) 1751-7370 (eISSN)
Vol. 20 1 wrag010EMBARK: Establishing a Monitoring Baseline for Antibiotic Resistance in Key environments
Swedish Research Council (VR) (2019-00299), 2022-05-01 -- 2023-12-31.
Surveillance for Emerging Antimicrobial Resistance through Characterization of the uncharted Environmental Resistome
Swedish Research Council (VR) (2023-01721), 2023-12-01 -- 2026-11-30.
Predicting future pathogenicity and antibiotic resistance
Swedish Foundation for Strategic Research (SSF) (FFL21-0174), 2022-08-01 -- 2027-12-31.
Subject Categories (SSIF 2025)
Infectious Medicine
Microbiology in the Medical Area
Microbiology
DOI
10.1093/ismejo/wrag010
PubMed
41603547
Related datasets
RemiGSC/Mgf_FDC: Cefiderocol resistance studied using Functional metagenomics [dataset]
URI: https://zenodo.org/records/15487633