Gfa, a new integron-borne fosfomycin resistance family
- 1IMIBIC
Abstract
Fosfomycin is increasingly used to treat multidrug-resistant Gram-negative infections, yet resistance surveillance largely relies on homology-based detection of known fos genes. Here, we identify Gfa, a previously unrecognized integron-borne fosfomycin resistance determinant uncovered through functional screening of 129 integron gene cassettes. Gfa confers high-level fosfomycin resistance across Enterobacterales and Pseudomonas aeruginosa and is resistant to phosphonoformate inhibition. Structural modelling and mutagenesis reveal a conserved cysteine-rich, zinc-organized architecture essential for activity and distinct from canonical Fos enzymes. Crude-extract assays confirm glutathione-dependent fosfomycin inactivation under metal-chelating conditions. Distant Gfa homologs also conferred resistance, although activity was restricted to a subset of proteins tested. Together, these findings establish Gfa as a previously unrecognized fosfomycin resistance family and highlight the limitations of homology-based mining for discovering novel resistance determinants and predicting which family members are functional.
Related
- Metallo-β-lactamase mediated resistance and Class 1 integron in carbapenem-resistant Enterobacterales isolates from the clinical specimens of Nepal
- Integrated genomic analyses reveal hierarchical organisation of quantitative resistance to biologically distinct soil-borne pathogens in wheat
- Pathogenome and Plasmid-Borne Antimicrobial Resistance Phenotypes in a Multidrug-Resistant O111:H8 Shiga Toxin-Producing Escherichia coli Strain
- Conservation and plasticity of IncHI2 plasmid-borne metal resistance loci in Salmonella enterica Serovar Heidelberg
- Screening for Pea Seed-borne Mosaic Virus Resistance (PSbMV) in Lentil and Development of Associated KASP Markers
BibTeX
@misc{kieffer2026integronborne,
title = {{Gfa, a new integron-borne fosfomycin resistance family}},
author = {N. Kieffer and A. Prieto and L. Ortiz-Miravalles and A. Hipolito and E. Vergara and J. Borrero del Pino and A. Carvalho and J.-A. Escudero},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757220},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757220v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Gfa, a new integron-borne fosfomycin resistance family
AU - N. Kieffer
AU - A. Prieto
AU - L. Ortiz-Miravalles
AU - A. Hipolito
AU - E. Vergara
AU - J. Borrero del Pino
AU - A. Carvalho
AU - J.-A. Escudero
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757220
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757220v1
AB - Fosfomycin is increasingly used to treat multidrug-resistant Gram-negative infections, yet resistance surveillance largely relies on homology-based detection of known fos genes. Here, we identify Gfa, a previously unrecognized integron-borne fosfomycin resistance determinant uncovered through functional screening of 129 integron gene cassettes. Gfa confers high-level fosfomycin resistance across Enterobacterales and Pseudomonas aeruginosa and is resistant to phosphonoformate inhibition. Structural modelling and mutagenesis reveal a conserved cysteine-rich, zinc-organized architecture essential for activity and distinct from canonical Fos enzymes. Crude-extract assays confirm glutathione-dependent fosfomycin inactivation under metal-chelating conditions. Distant Gfa homologs also conferred resistance, although activity was restricted to a subset of proteins tested. Together, these findings establish Gfa as a previously unrecognized fosfomycin resistance family and highlight the limitations of homology-based mining for discovering novel resistance determinants and predicting which family members are functional.
ER -