The Mechanism of Action of Fosfomycin (Phosphonomycin)

Kahan, Frederick M.; Kahan, J. S.; Cassidy, Patrick J.; Kropp, Helmut

doi:10.1111/j.1749-6632.1974.tb43277.x

Cited by 744 publications

(660 citation statements)

References 26 publications

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“…1,2 It irreversibly inhibits MurA (UDP-N-acetylglucosamine-3-enolpyruvyltransferase), an important enzyme in bacterial cell wall biosynthesis (Scheme 1). 3 This inhibition is achieved through alkylation of an active-site cysteine residue, which performs a nucleophilic attack on the C2 atom of fosfomycin. 3−5 Fosfomycin resistance proteins perform enzymatic modification and inactivation of the antibiotic to lower the clinical efficacy and therefore serve as potential targets for inhibitor design.…”

Section: Introductionmentioning

confidence: 99%

Determinants of Regioselectivity and Chemoselectivity in Fosfomycin Resistance Protein FosA from QM/MM Calculations

Liao

Thiel

2013

J. Phys. Chem. B

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FosA is a manganese-dependent enzyme that utilizes a Mn 2+ ion to catalyze the inactivation of the fosfomycin antibiotic by glutathione (GSH) addition. We report a theoretical study on the catalytic mechanism and the factors governing the regioselectivity and chemoselectivity of FosA. Density functional theory (DFT) calculations on the uncatalyzed reaction give high barriers and almost no regioselectivity even when adding two water molecules to assist the proton transfer. According to quantum mechanics/molecular mechanics (QM/MM) calculations on the full solvated protein, the enzyme-catalyzed glutathione addition reaction involves two major chemical steps that both proceed in the sextet state: proton transfer from the GSH thiol group to the Tyr39 anion and nucleophilic attack by the GSH thiolate leading to epoxide ring-opening. The second step is rate-limiting and is facilitated by the presence of the high-spin Mn 2+ ion that functions as a Lewis acid and stabilizes the leaving oxyanion through direct coordination. The barrier for C1 attack is computed to be 8.9 kcal/mol lower than that for C2 attack, in agreement with the experimentally observed regioselectivity of the enzyme. Further QM/MM calculations on the alternative water attack predict a concerted mechanism for this reaction, where the deprotonation of water, nucleophilic attack, and epoxide ring-opening take place via the same transition state. The calculated barrier is 8.3 kcal/mol higher than that for GSH attack, in line with the observed chemoselectivity of the enzyme, which manages to catalyze the addition of GSH in the presence of water molecules around its active site. The catalytic efficiency, regioselectivity, and chemoselectivity of FosA are rationalized in terms of the influence of the active-site protein environment and the different stabilization of the distorted substrates in the relevant transition states.

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Section: Introductionmentioning

confidence: 99%

Determinants of Regioselectivity and Chemoselectivity in Fosfomycin Resistance Protein FosA from QM/MM Calculations

Liao

Thiel

2013

J. Phys. Chem. B

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“…The glycerophosphate transport system is widespread in the bacterial world, while the hexose phosphate uptake system is confined to Staphylococcus spp and Enterobacteriaceae (with the exception of Proteus spp). [85][86][87] Once inside the cell, fosfomycin acts as an analog of phosphoenolpyruvate and inhibits enolpyruvyl transferase (also known as MurA), a cytoplasmic enzyme that allows the first step of synthesis of N-acetylmuramic acid. 86,[88][89][90][91] Because N-acetylmuramic acid is a major component of glycan strands in the cell wall, fosfomycin blocks cell wall synthesis with a lethal effect.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…[85][86][87] Once inside the cell, fosfomycin acts as an analog of phosphoenolpyruvate and inhibits enolpyruvyl transferase (also known as MurA), a cytoplasmic enzyme that allows the first step of synthesis of N-acetylmuramic acid. 86,[88][89][90][91] Because N-acetylmuramic acid is a major component of glycan strands in the cell wall, fosfomycin blocks cell wall synthesis with a lethal effect. 86,92,93 …”

Section: Mechanism Of Actionmentioning

confidence: 99%

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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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“…Fosfomycin inhibits the first step of peptidoglycan biosynthesis by binding to UDP-N-acetylglucosamine enolpyruvyl transferase. 6 It has shown high in vitro antimicrobial activity against S. aureus isolates, regardless of the presence of methicillin-resistance. 7,8 The objective of this study was to evaluate the in vitro interaction between minocycline and fosfomycin against MRSA isolates.…”

Section: Introductionmentioning

confidence: 99%

In vitro activity of minocycline combined with fosfomycin against clinical isolates of methicillin-resistant Staphylococcus aureus

et al. 2011

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This study aimed to evaluate the in vitro activity of minocycline combined with fosfomycin against isolates of methicillinresistant Staphylococcus aureus (MRSA). A total of 87 clinical isolates of MRSA collected from three Chinese hospitals were included in the study. The checkerboard method with determination of the fractional IC index (FICI) was used to determine whether antibiotic combinations act synergistically against these isolates. The susceptibility results for minocycline and fosfomycin were interpreted according to the most relevant criteria. The results demonstrated the following interactions: 76 isolates (87.4%) showed synergistic interactions (FICIp0.5) and 11 isolates (12.6%) showed indifferent interactions (0.5oFICIo4). No antagonistic interactions (FICIX4) were observed. The combination of minocycline and fosfomycin can be synergistic against MRSA. Further studies are required to determine the potential clinical role of this combination regimen as a therapeutic alternative for certain types of MRSA infections.

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The Mechanism of Action of Fosfomycin (Phosphonomycin)

Cited by 744 publications

References 26 publications

Determinants of Regioselectivity and Chemoselectivity in Fosfomycin Resistance Protein FosA from QM/MM Calculations

Determinants of Regioselectivity and Chemoselectivity in Fosfomycin Resistance Protein FosA from QM/MM Calculations

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

In vitro activity of minocycline combined with fosfomycin against clinical isolates of methicillin-resistant Staphylococcus aureus

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