Antibiotics fosfomycin

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. 

The absence of a sensitive microbial target is also a form of genetic intrinsic resistance. The oxirane antibiotic fosfomycin covalently modifies the target protein MurA on a sensitive and catalytically relevant Cys residue (Fig. 1) (10). MurA catalyzes the formation of Al-acetyhnuramic acid via enoylpyru-vyl transfer of phosphoenol pyruvate onto the acceptor sugar... 

Figure 1 The action of the antibiotic fosfomycin requires an active-site Cys residue in the target MurA. Substitution of Asp for Cys in some bacterial species results in intrinsic fosfomycin resistance.

CT. Characterization of a CysllS to Asp substitution in the Escherichia coli cell wall biosynthetic enzyme UDP-GlcNAc enolpymvyl transferase (MurA) that confers resistance to in- 32. activation by the antibiotic fosfomycin. Biochemistry 1996 35 4923 928. 33. 

Fosfomycin has relatively low toxicity. Its penetration into tissues, including bones and joints, and into the cerebrospinal fluid is good. When given orally (2-3 g/day), it can produce gastrointestinal distress when injected intramuscularly, it can cause local pain. Fosfomycin is recommended in daily doses of 4-16 g intravenously for the treatment of severe infections resistant to other commonly used antibiotics. Fosfomycin diffuses moderately well into bone tissue (2). 

Partial reduction of the triple bond is used for the selective conversion of dialkyl 1-alkynylphosphonates into f/.v-l-alkcnylphosphonatcs. The first racemic synthesis of the antibiotic fosfomycin in 1969 serves as an illustration. The methodology is based on the stereospecific reduction of dibutyl... 

Ishizawa, T., S. Sadahiro, K. Hosoi, I. Tamai, T. Terasaki, and A. Tsuji. 1992. Mechanisms of intestinal absorption of the antibiotic, fosfomycin, in brush-border membrane vesicles in rabbits and humans. /. Pharmacobio-Dynamics 15 481-489. 

The antibiotic fosfomycin works by interfering with bacterial cell-wall synthesis through oxacyclopropane ring opening. Thus, the enzyme crucial for wall construction is deactivated by reaction of the SH group of one of its cysteine amino acids (for structure, see Problem 45 of Chapter 2) with the strained ether function. 

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]. 

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. 

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. 

Fosfomycin (Monurol) Antibiotic Fosinopril (Monopril) ACE-inhibitor... 

Fosfomycin (Monurol) [Antibiotic] Uses Uncomplicated UTl Action -1- CeU w l synth Dose 3 g PO in 90-120 mL of H2O single dose X in renal impair Caution [B, ] -t Absorption w/ antacids/Ca salts Contra Component sensitivity Disp Granules SE HA, GI upset Interactions X Effects W/ antacids, metoclopramide EMS Monitor ECG and BP for signs of hypovolemia and electrolyte disturbances d/t D OD May cause impaired coordination, hearing loss and bitt taste in mouth symptomatic and supportive... 

Various antibiotics bacitracin chloramphenicol colistimethate sodium fosfomycin tromethamine fusidic acid metronidazole polymyxin B sulfate rifabutin sodium fusidate... 

The biosynthesis of cell wall peptidoglycan, showing the sites of action of five antibiotics (shaded bars 1 = fosfomycin, 2 = cycloserine, 3 = bacitracin, 4 = vancomycin, 5 = 3-lactam antibiotics). Bactoprenol (BP) is the lipid membrane carrier that transports building blocks across the cytoplasmic membrane M, N-acetylmuramic acid Glc, glucose NAcGIc or G, /V-acetylglucosamine. 

Among P-C bonded compounds, Fosfomycin and Bialaphos are well known (Fig. 1). They are obtained from fermentation broth and act as antibiotics and herbicides. 

An IPC-ESI-MS/MS method allowed the simultaneous determination of neomycin and bacitracin in human and rabbit sera [79] and the analysis of aminoglycoside antibiotics in human plasma [80]. IPC was recently validated for the estimation of bulk and formulated gatifloxacin [81]. The IPC determination of norfloxacin in diverse matrices worked as a stability indicating method [82], A CI2 stationary phase with embedded polar group successfully achieved IPC baseline tetracycline separation simply by using a phosphate as the IPR [83], A practical IPC method for the quality control of fosfomycin calcium and its related substances was recently suggested [84],... 

Fosfomycin is a broad-spectrum antibiotic used to treat uncomplicated lower urinary tract infections. It penetrates interstitial space fluids of soft tissues well and reaches concentrations sufficient to substantially inhibit the growth of relevant bacteria at the target site (1). 

Fukuyama M, Furuhata K, Oonaka K, Kara T, Sunakawa K. [Antibacterial activity of fosfomycin against the causative bacteria isolated from bacterial enteritis.] Jpn J Antibiot 2000 53(7) 522-31. 

Yoshiyama Y, Yazaki T, Wong PC, Beauchamp D, Kanke M. The effect of fosfomycin on glycopeptide antibiotic-induced nephrotoxicity in rats. J Infect Chemother 2001 7(4) 243-6. 

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