Abstract
ABSTRACTFosfomycin is a decades-old antibiotic which is being revisited because of its perceived activity against many extensively drug-resistant Gram-negative pathogens. FosA proteins are Mn2+ and K+-dependent glutathione S-transferases which confer fosfomycin resistance in Gram-negative bacteria by conjugation of glutathione to the antibiotic. Plasmid-borne fosA variants have been reported in fosfomycin-resistant Escherichia coli strains. However, the prevalence and distribution of fosA in other Gram-negative bacteria are not known. We systematically surveyed the presence of fosA in Gram-negative bacteria in over 18,000 published genomes from 18 Gram-negative species and investigated their contribution to fosfomycin resistance. We show that FosA homologues are present in the majority of genomes in some species (e.g., Klebsiella spp., Enterobacter spp., Serratia marcescens, and Pseudomonas aeruginosa), whereas they are largely absent in others (e.g., E. coli, Acinetobacter baumannii, and Burkholderia cepacia). FosA proteins in different bacterial pathogens are highly divergent, but key amino acid residues in the active site are conserved. Chromosomal fosA genes conferred high-level fosfomycin resistance when expressed in E. coli, and deletion of chromosomal fosA in S. marcescens eliminated fosfomycin resistance. Our results indicate that FosA is encoded by clinically relevant Gram-negative species and contributes to intrinsic fosfomycin resistance.
Highlights
Fosfomycin is a decades-old antibiotic which is being revisited because of its perceived activity against many extensively drug-resistant Gram-negative pathogens
FosA was frequently identified in the genomes of Providencia stuartii (100%), K. pneumoniae (99.7%), S. marcescens (99.7%), Pseudomonas aeruginosa (98.8%), Enterobacter aerogenes (98.4%), Klebsiella oxytoca (96.6%), Morganella morganii (90.5%), Providencia rettgeri (85.7%), and Enterobacter cloacae (82.4%), which were likely to be on the chromosomes based on the high prevalence (Table 1)
Homologues of FosA were identified in most genomes of K. pneumoniae, K. oxytoca, E. cloacae, E. aerogenes, S. marcescens, M. morganii, P. stuartii, and P. aeruginosa, which represent species with intrinsic resistance or reduced susceptibility to fosfomycin [4, 6]
Summary
Fosfomycin is a decades-old antibiotic which is being revisited because of its perceived activity against many extensively drug-resistant Gram-negative pathogens. We show that fosA genes, which encode dimeric Mn2ϩ- and Kϩ-dependent glutathione S-transferase, are widely distributed in the genomes of Gram-negative bacteria— those belonging to the family Enterobacteriaceae—and confer fosfomycin resistance. This finding suggests that chromosomally located fosA genes represent a vast reservoir of fosfomycin resistance determinants that may be transferred to E. coli. They suggest that inhibition of FosA activity may provide a viable strategy to potentiate the activity of fosfomycin against XDR Gram-negative bacteria. Insights into FosA-mediated intrinsic fosfomycin resistance in Gram-negative bacteria would inform approaches to potentiate the activity of fosfomycin against extensively drug-resistant (XDR) Gram-negative bacteria
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