Phosphonomycin, a New Antibiotic Produced by Strains of
            <i>Streptomyces</i>

Hendlin, David; Stapley, E. O.; Jackson, M.; Wallick, H; Miller, A. Kathrine; Wolf, Frank J.; Miller, Thomas W.; Chaiet, Louis; Kahan, Frederick M.; Foltz, Elwood L.; Woodruff, H. B.; Mata, J. M.; Hernandez, Sebastian; Mochales, S.

doi:10.1126/science.166.3901.122

Cited by 554 publications

(314 citation statements)

References 7 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.…”

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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“…Fosfomycin, originally isolated in 1969 as a product of Streptomyces spp. [1], could prove to be such an example. Several studies have shown that fosfomycin has retained substantial antimicrobial activity against 'problem'…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections

Roussos

Karageorgopoulos

Samonis

et al. 2009

International Journal of Antimicrobial Agents

162

151

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“…1). Initially released by a few bacterial species, such as Streptomyces spp [26][27][28] or Pseudomonas syringae, 29 it is now produced synthetically for pharmaceutical purposes. The disodium salt is administered parenterally and the trometamine salt orally.…”

Section: Pharmacokinetics and Pharmacodynamics Descriptionmentioning

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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Phosphonomycin, a New Antibiotic Produced by Strains of Streptomyces

Abstract: Phosphonomycin is a newly discovered antibiotic produced by streptomycetes. It is effective, when administered by the oral route, to mice infected with Gram-positive or Gram-negative microorganisms. The antibiotic is bactericidal and inhibits cell-wall synthesis.

Cited by 554 publications

References 7 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

Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections

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

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