Mutations that inactivate the nonessential glycerophosphate transporter render bacteria resistant to fosfomycin.Prescribing fosfomycin together with at least another active drug reduces the risk of developing bacterial resistance. Fosfomycin acts synergistically with many other antibiotics, including aminoglycosides, carbapenems, cephalosporins, daptomycin and oritavancin. Enzymes conferring resistance to fosfomycin have also been identified and are encoded both chromosomally and on plasmids.Three related fosfomycin resistance enzymes (named FosA, FosB, and FosX) are members of the glyoxalase superfamily. These enzymes function by nucleophilic attack on carbon 1 of fosfomycin, which opens the epoxide ring and renders the drug ineffective. The enzymes differ by the identity of the nucleophile used in the reaction: glutathione for FosA, bacillithiol for FosB, and water for FosX.In general, FosA and FosX enzymes are produced by Gram-negative bacteria, whereas FosB is produced by Gram-positive bacteria.FosC uses ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective. Side effects
The drug is well tolerated and has a low incidence of harmful side effects. Mechanism of action
Despite its name (ending in -omycin) Fosfomycin is not a macrolide, but a member of a novel class of phosphonic antibiotics. Fosfomycin is bactericidal and inhibits bacterial cell wall biogenesis by inactivating the enzyme UDP-N-acetylglucosamine-3-enolpyruvyltransferase, also known as MurA. This enzyme catalyzes the committed step in peptidoglycan biosynthesis, namely the ligation of phosphoenolpyruvate (PEP) to the 3-hydroxyl group of UDP-N-acetylglucosamine. This pyruvate moiety provides the linker that bridges the glycan and peptide portion of peptidoglycan.
Fosfomycin is a PEP analog that inhibits MurA by alkylating an active site cysteine residue (Cys 115 in the Escherichia coli enzyme).Fosfomycin enters the bacterial cell through the glycerophosphate transporter. History
Fosfomycin (originally known as phosphonomycin) was discovered in a joint effort of Merck and Co. and Spains Compañía Española de Penicilina y Antibióticos (CEPA). It was first isolated by screening broth cultures of Streptomyces fradiae isolated from soil samples for the ability to cause formation of spheroplasts by growing bacteria. The discovery was described in a series of papers published in 1969. CEPA began producing fosfomycin on an industrial scale in 1971 at its Aranjuez facility. Manufacture
The complete fosfomycin biosynthetic gene cluster from Streptomyces fradiae has been cloned and sequenced and the heterologous production of fosfomycin in S. lividans has been achieved by Ryan Woodyer of the Huimin Zhao and Wilfred van der Donk research groups.Large scale production of fosfomycin is achieved by making an epoxide of cis-propenylphosphonic acid to yield racemic mixture fosfomycin. References
External links
"Fosfomycin". Drug Information Portal. U.S. National Library of Medicine.