Molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli

Takahata, Sho; Ida, Takashi; Hiraishi, Toru; Sakakibara, Shiro; Maebashi, Kazunori; Terada, Shinichi; Muratani, Tetsuro; Matsumoto, Tetsuro; Nakahama, Chikara; Tomono, Kazunori

doi:10.1016/j.ijantimicag.2009.11.011

Cited by 164 publications

(179 citation statements)

References 29 publications

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“…A mutation in murA of E. coli was isolated after mutagenesis (Wu and Venkateswaran 1974) and counterselection against transport mutants and two murA mutants of E. coli were reported among clinical isolates in a Japanese study (Takahata et al 2010) It is likely that, in vitro, the frequency of transport mutants is so great relative to target mutants that they are not generally seen. The finding of murA mutants with clinical isolates of E. coli might reflect the low fitness of in vitro transport mutants.…”

Section: Mutational Resistancementioning

confidence: 99%

Fosfomycin: Mechanism and Resistance

Silver¹

2017

Cold Spring Harb Perspect Med

231

169

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Section: Mutational Resistancementioning

confidence: 99%

Fosfomycin: Mechanism and Resistance

Silver¹

2017

Cold Spring Harb Perspect Med

231

169

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“…Susceptibility to fosfomycin can be affected by expression of the genes encoding GlpT, UhpT, and MurA. In some E. coli studies, mutations in genes encoding the positive regulators of uhpT expression, UhpA and CyaA, conferred resistance because the mutants had reduced uptake of fosfomycin (14,15). Other studies showed that a clinical isolate resistant to fosfomycin produces a MurA variant that results in overexpression of MurA (16).…”

mentioning

confidence: 99%

Elevated Expression of GlpT and UhpT via FNR Activation Contributes to Increased Fosfomycin Susceptibility in Escherichia coli under Anaerobic Conditions

Kurabayashi

Tanimoto

Fueki

et al. 2015

Antimicrob Agents Chemother

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Because a shortage of new antimicrobial agents is a critical issue at present, and with the spread of multidrug-resistant (MDR) pathogens, the use of fosfomycin to treat infections is being revisited as a "last-resort option." This drug offers a particular benefit in that it is more effective against bacteria growing under oxygen-limited conditions, unlike other commonly used antimicrobials, such as fluoroquinolones and aminoglycosides. In this study, we showed that Escherichia coli strains, including enterohemorrhagic E. coli (EHEC), were more susceptible to fosfomycin when grown anaerobically than when grown aerobically, and we investigated how the activity of this drug was enhanced during anaerobic growth of E. coli. Our quantitative PCR analysis and a transport assay showed that E. coli cells grown under anaerobic conditions had higher levels of expression of glpT and uhpT, encoding proteins that transport fosfomycin into cells with their native substrates, i.e., glycerol-3-phosphate and glucose-6-phosphate, and led to increased intracellular accumulation of the drug. Elevation of expression of these genes during anaerobic growth requires FNR, a global transcriptional regulator that is activated under anaerobic conditions. Purified FNR bound to DNA fragments from regions upstream of glpT and uhpT, suggesting that it is an activator of expression of glpT and uhpT during anaerobic growth. We concluded that the increased antibacterial activity of fosfomycin toward E. coli under anaerobic conditions can be attributed to elevated expression of GlpT and UhpT following activation of FNR, leading to increased uptake of the drug.

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“…98 However, resistance to fosfomycin due to overexpression of enolpyruvyl transferase has been also observed. 96 Several modifying enzymes have been described, sometimes in species that could produce this antibiotic, 99 but also in strains that harbor plasmidic or chromosomal resistance. In all cases, they lead to the formation of inactive adducts:…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

“…85,86,113,114 They may be associated with mutations in their regulatory genes, such as uhpA (encoding a regulator protein required for activation of the uhpT promoter), or ptsI and cyaA, the products of which are involved in the synthesis of cyclic AMP and therefore regulate the level of glycerophosphate transport. 96,[114][115][116] Although many mechanisms of resistance to fosfomycin have been described since its discovery, mutations of fecal E. coli strains during treatment of uncomplicated acute cystitis do not appear to be clinically relevant, which sets them apart from the fluoroquinolones. 117 For some authors, the observation that fosfomycin resistance does not increase with the passage of time could be due to the fact that mutations in murA and in transport systems have a biological cost which is not compatible with their persistence in the community.…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

Fosfomycin and Its Application in the Treatment of Multidrug-Resistant Enterobacteriaceae Infections

2011

Clinical Medicine Reviews in Therapeutics

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Abstract:The use of fosfomycin has been limited in therapeutics in recent years. Because it has shown good antibacterial activity in vitro and clinical efficacy in some domains, it has been proposed as an alternative to current antimicrobial agents, which are subject to increasing resistance. This paper reviews the main properties of fosfomycin and the latest publications concerning multidrugresistant Enterobacteriaceae infections. In uncomplicated urinary tract infections, a single oral dose was found to be safe and effective. In complicated urinary tract infections, the same results were observed with several doses. In both cases, by using fosfomycin to treat infections, the use of carbapenems could be reduced, leading to lower costs and better microbial ecology. In severe infections, combinations with intravenous fosfomycin need to be explored further because its future activity may depend on choosing a good partner drug. Because of the fast evolution of microbial resistance, more studies are urgently needed.

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Molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli

Cited by 164 publications

References 29 publications

Fosfomycin: Mechanism and Resistance

Fosfomycin: Mechanism and Resistance

Elevated Expression of GlpT and UhpT via FNR Activation Contributes to Increased Fosfomycin Susceptibility in Escherichia coli under Anaerobic Conditions

Fosfomycin and Its Application in the Treatment of Multidrug-Resistant Enterobacteriaceae Infections

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