Plasmid-encoded fosfomycin resistance

Súarez, Juan E.; Mendoza, M. C.

doi:10.1128/aac.35.5.791

Cited by 83 publications

(55 citation statements)

References 56 publications

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“…Moreover, fosfomycin does not appear to be a substrate for common mechanisms of multidrug resistance such as multidrug efflux pumps [13,14]. In addition, the main type of resistance to fosfomycin appears to be chromosomal rather than plasmid-mediated [15], which diminishes the likelihood of co-transmission of resistance to fosfomycin along with resistance to other agents.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin

Falagas

Maraki

Karageorgopoulos

et al. 2010

International Journal of Antimicrobial Agents

159

107

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The advancing antimicrobial drug resistance among Enterobacteriaceae renders the evaluation of potential novel therapeutic options necessary. We sought to evaluate the in vitro antimicrobial activity of fosfomycin against multidrug-resistant (MDR) Enterobacteriaceae isolates. Antimicrobial susceptibility to fosfomycin and 12 additional antibiotics of MDR Enterobacteriaceae isolates collected between November 2007 and April 2009 at the University Hospital of Heraklion, Crete, Greece, was examined using the Etest method. A total of 152 MDR Enterobacteriaceae isolates were studied, including Klebsiella pneumoniae (76.3%), Escherichia coli (17.1%), Proteus mirabilis (4.6%) and other species (2.0%).Antimicrobial susceptibility rates were highest for fosfomycin (92.8%), tigecycline (92.1%) and colistin (73.0%) followed by imipenem (35.5%), tetracycline (20.4%), gentamicin (19.7%), trimethoprim/sulfamethoxazole (12.5%) and ciprofloxacin (10.5%). Of the 152 isolates, 85 (55.9%) were extensively drug-resistant (XDR), of which 78 (91.8%) remained susceptible to fosfomycin. Susceptibility to fosfomycin of the 79 carbapenemase-producing, 34 extended-spectrum -lactamase-producing and 24 metallo--lactamase-producing isolates was 94.9%, 94.1% and 83.3%, respectively. In conclusion, in this study fosfomycin exhibited good in vitro antimicrobial activity against MDR and XDR Enterobacteriaceae. We suggest further evaluation of the potential clinical utility of fosfomycin against infections caused by these pathogens.

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Section: Discussionmentioning

confidence: 99%

Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin

Falagas

Maraki

Karageorgopoulos

et al. 2010

International Journal of Antimicrobial Agents

159

107

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“…FosA is a glutathione-S-transferase present on transposon TN2921 originally found on a plasmid in S. marcescens (Suárez and Mendoza 1991), using Mn 2þ and K þ as metal cofactors; other related glutathione transferase (FosA type) enzymes found to be plasmid-borne are FosA3, FosA4, FosA5, and FosC2. A related FosA enzyme is found encoded in the chromosome of P. aeruginosa.…”

Section: Fosfomycin-modifying Enzymesmentioning

confidence: 99%

Fosfomycin: Mechanism and Resistance

Silver¹

2017

Cold Spring Harb Perspect Med

241

169

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“…Furthermore, the residues highlighted in this channel (with the exception of Trp 46 ) contain a hydroxyl or thiol side chain that could be involved in activating and/or stabilizing GSH/GS Ϫ . The low toxicity and broad-spectrum bactericidal activity of fosfomycin have resulted in its increased clinical use, which in turn has resulted in fosfomycin-resistant strains (7,8). Currently, there are no inhibitors to combat FosA-mediated fosfomycin resistance.…”

mentioning

confidence: 99%

Functional Analysis of Active Site Residues of the Fosfomycin Resistance Enzyme FosA from Pseudomonas aeruginosa

Beharry

Palzkill

2005

Journal of Biological Chemistry

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The metalloglutathione transferase FosA catalyzes the conjugation of glutathione to carbon-1 of the antibiotic fosfomycin, rendering it ineffective as an antibacterial drug. Codon randomization and selection for the ability of resulting clones to confer fosfomycin resistance to Escherichia coli were used to identify residues critical for FosA function. Of the 24 codons chosen for randomization, 16 were found to be essential because only the wild type amino acid was selected. These included ligands to the Mn 2؉ and the K ؉ , residues that furnish hydrogen bonds to fosfomycin, and residues located in a putative glutathione/fosfomycin-binding site. The remaining eight positions randomized were tolerant to substitutions. Site-directed mutagenesis of some of the essential and tolerant amino acids to alanine was performed, and the activity of the purified proteins was determined. Mutation of the residues that are within hydrogen bonding distance to the oxirane or phosphonate oxygens of fosfomycin resulted in variants with very low or no activity. Mutation of Ser 94 , which bridges one of the phosphonate oxygens with a potassium ion, resulted in insoluble protein. The Y39A mutation in the putative glutathione-binding site resulted in a 4-fold increase in the apparent K m for glutathione. Only two of the amino acids in the substrate-binding site are conserved in the related fosfomycin resistance proteins FosB and FosX, whereas no amino acids in the putative glutathione-binding site are conserved.

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Plasmid-encoded fosfomycin resistance

Cited by 83 publications

References 56 publications

Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin

Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin

Fosfomycin: Mechanism and Resistance

Functional Analysis of Active Site Residues of the Fosfomycin Resistance Enzyme FosA from Pseudomonas aeruginosa

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