Fosfomycin

Fosfomycin is one of a few natural products containing a carbon-phosphorus (C— P) bond isolated from Streptomyces fradiae, Streptomyces viridochromogenes, and Streptomyces wedmorensis [73]. It was also isolated from Pseudomonas syringae and Pseudomonas viridiflava [74, 75], Fosfomycin is a highly effective antibiotic of low toxicity clinically utilized for the treatment of lower urinary tract infections [76] as well as methicillin-resistant [77] and vancomycin-resistant [78] strains of S. aureus. Moreover, fosfomycin is effective for the treatment of cephalosporin- and penicillin-resistant Streptococcus pneumonia [79] and ciprofloxacin-resistant E. coli [80], The antimicrobial activity of fosfomycin has been ascribed to the inactivation of UDP-GlcAAc-3-O-enolpyruvyltransferase (MurA), an essential enzyme that catalyzes the first committed step in the biosynthesis of peptidoglycan, the main component of the cell wall, by covalent alkylation of an active site cysteine [81]. 

the following information on the catalysis of HPPE in the fourth step leading to fosfomycin 95 from HPP 94 was reported (i) it was confirmed that the 

THREE-MEMBERED HETEROCYCLIC RINGS AND THEIR FUSED DERIVATIVES 

Very recently, the oxidative epoxidation reaction catalyzed by HPPE and leading to fosfomycin was probed with hybrid density functional theory (DFT)-quantum chemistry methods. Based on the available crystal structure of the HppE-Fell-substrate 

Originally called phosphonomycin, fosfomycin is a broad spectrum antibiotic produced by a 

Trede Name Manufacturer Country Year Introduced 

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There is also a fermentation route to Fosfomycin as noted by Kleeman Engel. 

Acetaldehyde Fosfomycin Methohexital sodium Mitopodozide Netilmicin... 

Fosfomycin is an antibiotic produced by several Streptomyces species [95, 96] as well as by the Gram-negative Pseudomonas syringiae and Pseudomonas viridiflava. dl, 98] As an analogue of phosphoenolpyruvate, it irreversibly inhibits UDP-N-acetylglu-cosamine-3-O-enolpymvyltransferase (MurA), the enzyme that catalyzes the first step in peptidoglycan biosynthesis [99]. 

Scheme 10.26 Partial biosynthetic pathway of fosfomycin and bialaphos. Both pathways use a homologous set of enzymes for the synthetic steps leading from phosphoenolpyruvate (PEP) to phosphonoacetaldehyde (PAA). The conversion of hydroxypropylphosphonic acid (HPP) to fosfomycin is catalyzed by the epoxidase HppE. Propenylphosphonic acid (PPA), however, is not converted to fosfomycin.

Lactams Penicillins Cephalosporins Monobactams Carbapenems Vancomycin Bacitracin Cycloserin Fosfomycin Inhibition of synthesis of, or damage to, cell wall... 

Fos Fosfomycin Gram-negative and gram-positive bacteria Plasmid... 

Furthermore, if the antibiotic passes membranes through a specific port of entry, its mutational loss leads to resistance. The lack of the outer membrane protein OprD in P. aeruginosa causes resistance to the (3-lactam antibiotic imipenem. Fosfomycin passes the cytoplasmic membrane via an L-a-glycerol phosphate permease. This transport system is not essential for bacterial growth and therefore mutants with a reduced expression are frequently selected under therapy. 

Examples of urinary anti-infectives include cinoxacin (Cinobac), fosfomycin (Monurol), metlienamine rnande-late (Mandelamine), nalidixic acid (NegGram), and nitrofurantoin (Puradantin). 

Fosfomycin is bactericidal and interferes witii bacterial cell wall syndiesis. Fosfomycin is used for UTIs tiiat are caused by susceptible microorganisms. Adverse reactions that may occur with fosfomycin include headache, dizziness, nausea, abdominal cramps, and vaginitis. 

Fosfomycin is contraindicated in patients with a hypersensitivity to the drug. Fosfomycin is used cautiously during pregnancy (Pregnancy Category B) and lactation. There is a lowered plasma concentration and urinary tract excretion when fosfomycin is administered with metoclopramide... 

Fosfomycin comes in dry fonn as a one-dose packet to be dissolved in 90 to 120 mL water (not hot water). Drink immediately after mixing and take with food to prevent gastric upset. 

What instruction would be most important to give a patient prescribed fosfomycin (Monurol) ... 

Fosfomycin inhibits pyruvil transferase, which is an enzyme involved in peptidoglycan synthesis. Two mechanisms of acquired resistance have been described for fosfomycin (Davies 1994). 

Plasmid- ortransposon-mediated resistance occurs by inactivation ofthe antibiotic. Fosfomycin is combined with glutathione intracellularly to produce a compound lacking in antibacterial activity. The gene encoding the enzyme catalysing this reaction has been designated/or-r. 

A second mechanism of acquired resistance to fosfomycin involves chromosomal mutations in sugar phosphate uptake pathways which are responsible for transporting fosfomycin into the cell. The alterations decrease accumulation of the antibiotic to levels below those required for inhibition. 

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