Widespread fosfomycin resistance in gram-negative bacteria attributable to the chromosomal fosA gene

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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 Gramnegative 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.

Original languageEnglish
Article numbere00749-17
JournalmBio
Volume8
Issue number4
DOIs
Publication statusPublished - 01-07-2017

Fingerprint

Fosfomycin
Gram-Negative Bacteria
Genes
Escherichia coli
Serratia marcescens
Genome
Anti-Bacterial Agents
Glutathione Transferase
Burkholderia cepacia
Acinetobacter baumannii
Enterobacter
Klebsiella
Infection
Urinary Tract Infections
Pharmaceutical Preparations
Pseudomonas aeruginosa
Glutathione
Catalytic Domain
Plasmids

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Virology

Cite this

Ito, R., Mustapha, M. M., Tomich, A. D., Callaghan, J. D., McElheny, C. L., Mettus, R. T., ... Doi, Y. (2017). Widespread fosfomycin resistance in gram-negative bacteria attributable to the chromosomal fosA gene. mBio, 8(4), [e00749-17]. https://doi.org/10.1128/mBio.00749-17
Ito, Ryota ; Mustapha, Mustapha M. ; Tomich, Adam D. ; Callaghan, Jake D. ; McElheny, Christi L. ; Mettus, Roberta T. ; Shanks, Robert M.Q. ; Sluis-Cremer, Nicolas ; Doi, Yohei. / Widespread fosfomycin resistance in gram-negative bacteria attributable to the chromosomal fosA gene. In: mBio. 2017 ; Vol. 8, No. 4.
@article{28164fe62cb041f1a9bd15d2e87edce9,
title = "Widespread fosfomycin resistance in gram-negative bacteria attributable to the chromosomal fosA 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 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 Gramnegative 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.",
author = "Ryota Ito and Mustapha, {Mustapha M.} and Tomich, {Adam D.} and Callaghan, {Jake D.} and McElheny, {Christi L.} and Mettus, {Roberta T.} and Shanks, {Robert M.Q.} and Nicolas Sluis-Cremer and Yohei Doi",
year = "2017",
month = "7",
day = "1",
doi = "10.1128/mBio.00749-17",
language = "English",
volume = "8",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "4",

}

Ito, R, Mustapha, MM, Tomich, AD, Callaghan, JD, McElheny, CL, Mettus, RT, Shanks, RMQ, Sluis-Cremer, N & Doi, Y 2017, 'Widespread fosfomycin resistance in gram-negative bacteria attributable to the chromosomal fosA gene', mBio, vol. 8, no. 4, e00749-17. https://doi.org/10.1128/mBio.00749-17

Widespread fosfomycin resistance in gram-negative bacteria attributable to the chromosomal fosA gene. / Ito, Ryota; Mustapha, Mustapha M.; Tomich, Adam D.; Callaghan, Jake D.; McElheny, Christi L.; Mettus, Roberta T.; Shanks, Robert M.Q.; Sluis-Cremer, Nicolas; Doi, Yohei.

In: mBio, Vol. 8, No. 4, e00749-17, 01.07.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Widespread fosfomycin resistance in gram-negative bacteria attributable to the chromosomal fosA gene

AU - Ito, Ryota

AU - Mustapha, Mustapha M.

AU - Tomich, Adam D.

AU - Callaghan, Jake D.

AU - McElheny, Christi L.

AU - Mettus, Roberta T.

AU - Shanks, Robert M.Q.

AU - Sluis-Cremer, Nicolas

AU - Doi, Yohei

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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 Gramnegative 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.

AB - 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 Gramnegative 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.

UR - http://www.scopus.com/inward/record.url?scp=85029167737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029167737&partnerID=8YFLogxK

U2 - 10.1128/mBio.00749-17

DO - 10.1128/mBio.00749-17

M3 - Article

C2 - 28851843

AN - SCOPUS:85029167737

VL - 8

JO - mBio

JF - mBio

SN - 2161-2129

IS - 4

M1 - e00749-17

ER -

Ito R, Mustapha MM, Tomich AD, Callaghan JD, McElheny CL, Mettus RT et al. Widespread fosfomycin resistance in gram-negative bacteria attributable to the chromosomal fosA gene. mBio. 2017 Jul 1;8(4). e00749-17. https://doi.org/10.1128/mBio.00749-17