Ryota Ito1, Mustapha M. Mustapha2,1, Adam D. Tomich1, Jake D. Callaghan3, Christi L. McElheny1, Roberta T. Mettus1, Robert M. Q. Shanks3, Nicolas Sluis‐Cremer2,1, Yohei Doi2,4,1
1Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
2Center for Innovative Antimicrobial Therapy, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
3Department of Ophthalmology, University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania USA
4Department of Microbiology, Fujita Health University, Aichi, Japan
Tóm tắt
ABSTRACT
Fosfomycin 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 Mn
2+
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.
IMPORTANCE
There is a critical need to identify alternate approaches to treat infections caused by extensively drug-resistant (XDR) Gram-negative bacteria. Fosfomycin is an old antibiotic which is routinely used for the treatment of urinary tract infections, although there is substantial interest in expanding its use to systemic infections caused by XDR Gram-negative bacteria. In this study, we show that
fosA
genes, which encode dimeric Mn
2+
- and K
+
-dependent glutathione
S
-transferase, are widely distributed in the genomes of Gram-negative bacteria—particularly 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
. Furthermore, they suggest that inhibition of FosA activity may provide a viable strategy to potentiate the activity of fosfomycin against XDR Gram-negative bacteria.
