Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal <italic toggle="yes">fosA</italic> Gene

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 Mn2+ and K+-dependent glutathione S-transferases which confer fosfomycin resistance in Gram-negative bacteria...

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Main Authors: Ryota Ito, Mustapha M. Mustapha, Adam D. Tomich, Jake D. Callaghan, Christi L. McElheny, Roberta T. Mettus, Robert M. Q. Shanks, Nicolas Sluis-Cremer, Yohei Doi
Format: Article
Language:English
Published: American Society for Microbiology 2017-09-01
Series:mBio
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Online Access:https://journals.asm.org/doi/10.1128/mBio.00749-17
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author Ryota Ito
Mustapha M. Mustapha
Adam D. Tomich
Jake D. Callaghan
Christi L. McElheny
Roberta T. Mettus
Robert M. Q. Shanks
Nicolas Sluis-Cremer
Yohei Doi
author_facet Ryota Ito
Mustapha M. Mustapha
Adam D. Tomich
Jake D. Callaghan
Christi L. McElheny
Roberta T. Mettus
Robert M. Q. Shanks
Nicolas Sluis-Cremer
Yohei Doi
author_sort Ryota Ito
collection DOAJ
description 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 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. 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 Mn2+- 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.
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spelling doaj.art-800591cac5b2456d90b934759a38ffd92022-12-21T20:34:44ZengAmerican Society for MicrobiologymBio2150-75112017-09-018410.1128/mBio.00749-17Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal <italic toggle="yes">fosA</italic> GeneRyota Ito0Mustapha M. Mustapha1Adam D. Tomich2Jake D. Callaghan3Christi L. McElheny4Roberta T. Mettus5Robert M. Q. Shanks6Nicolas Sluis-Cremer7Yohei Doi8Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADivision of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADivision of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADivision of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADivision of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADivision of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADivision of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAABSTRACT 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 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. 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 Mn2+- 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.https://journals.asm.org/doi/10.1128/mBio.00749-17Gram negativefosfomycin resistancegenomicsglutathione S-transferasephylogenetics
spellingShingle Ryota Ito
Mustapha M. Mustapha
Adam D. Tomich
Jake D. Callaghan
Christi L. McElheny
Roberta T. Mettus
Robert M. Q. Shanks
Nicolas Sluis-Cremer
Yohei Doi
Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal <italic toggle="yes">fosA</italic> Gene
mBio
Gram negative
fosfomycin resistance
genomics
glutathione S-transferase
phylogenetics
title Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal <italic toggle="yes">fosA</italic> Gene
title_full Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal <italic toggle="yes">fosA</italic> Gene
title_fullStr Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal <italic toggle="yes">fosA</italic> Gene
title_full_unstemmed Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal <italic toggle="yes">fosA</italic> Gene
title_short Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal <italic toggle="yes">fosA</italic> Gene
title_sort widespread fosfomycin resistance in gram negative bacteria attributable to the chromosomal italic toggle yes fosa italic gene
topic Gram negative
fosfomycin resistance
genomics
glutathione S-transferase
phylogenetics
url https://journals.asm.org/doi/10.1128/mBio.00749-17
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