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Fosfomycin
Systematic (IUPAC) name
[(2R,3S)-3-methyloxiran-2-yl]phosphonic acid
Identifiers
CAS number 23155-02-4 78964-85-9 (tromethamine)
ATC code J01XX01
PubChem 446987
DrugBank APRD00987
Chemical data
Formula C3H7O4P 
Mol. mass 138.059 g/mol
Pharmacokinetic data
Bioavailability 30–37% (oral, fosfomycin tromethamine); varies with food intake
Protein binding Nil
Metabolism Nil
Half life 5.7 hours (mean)
Excretion Renal and fecal, unchanged
Therapeutic considerations
Pregnancy cat. B(US)
Legal status -only (US)
Routes Oral
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Fosfomycin (also known as phosphomycin and phosphonomycin) is a broad-spectrum antibiotic[1] produced by certain Streptomyces species.

Contents

Uses

Fosfomycin is indicated in the treatment of urinary tract infections, where it is usually administered as a single oral megadose.[2]

The drug is well tolerated and has a low incidence of harmful side-effects.[2] However, development of bacterial resistance under therapy is a frequent occurrence and makes fosfomycin unsuitable for sustained therapy of severe infections.

Additional uses have been proposed.[3] The global problem of advancing antimicrobial resistance has led to a renewed interest in its use more recently.[4]

Mechanism of action

Fosfomycin is an antimetabolite of phosphoenolpyruvate in the enzymatic synthesis of N-acetylmuramic acid via enolpyruvate transferase (also known as MurA)[5], a component of the bacterial cell wall glycopeptide murein.[6] The epoxide ring of fosfomycin covalently reacts with a cysteine residue in the enzyme's active site, which results in the enzyme's irreversible inactivation.

Fosfomycin enters the bacterial cell through the glycerophosphate transporter.

Biosynthetic gene cluster

The complete fosfomycin biosynthetic gene cluster from Streptomyces fradiae has been cloned and sequenced and the heterologous production of fosfomycin in Streptomyces lividans has been achieved by Ryan Woodyer of the Huimin Zhao and Wilfred van der Donk research groups.[7]

Resistance

Mutations that inactivate the non-essential glycerophosphate transporter render bacteria resistant to fosfomycin.[8][9]

Fosfomycin resistance enzymes

Enzymes conferring resistance to fosfomycin have also been identified and are encoded both chromosomally and on plasmids.[10]

Glyoxalase superfamily enzymes

Three related but mechanistically distinct fosfomycin resistance enzymes (named, FosA, FosB and FosX) function by nucleophilic attack on carbon 1 of fosfomycin. This opens the epoxide ring and renders the drug ineffective. The enzymes differ by the identity of the nucleophile; glutathione for FosA, cysteine for FosB, and water for FosX.[10]

FosC

FosC utilizes ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective.[11]

See also

References

  1. ^ Grif K, Dierich MP, Pfaller K, Miglioli PA, Allerberger F (August 2001). "In vitro activity of fosfomycin in combination with various antistaphylococcal substances". The Journal of antimicrobial chemotherapy 48 (2): 209–17. PMID 11481290. http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11481290. 
  2. ^ a b Patel SS, Balfour, JA (1997). "Fosfomycin tromethamine: A review of its antibacterial activity, pharmakinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections". Drugs 53: 637–656. PMID 9098664. 
  3. ^ Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI (April 2008). "Fosfomycin: use beyond urinary tract and gastrointestinal infections". Clin. Infect. Dis. 46 (7): 1069–77. doi:10.1086/527442. PMID 18444827. http://www.journals.uchicago.edu/doi/abs/10.1086/527442?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov. 
  4. ^ Falagas ME, Grammatikos AP, Michalopoulos A. Potential of old-generation antibiotics to address current need for new antibiotics. Expert Rev Anti Infect Ther. 2008; 6(5):593-600 PMID:18847400
  5. ^ Brown ED, Vivas EI, Walsh CT, Kolter R (July 1995). "MurA (MurZ), the enzyme that catalyzes the first committed step in peptidoglycan biosynthesis, is essential in Escherichia coli". J. Bacteriol. 177 (14): 4194–7. PMID 7608103. 
  6. ^ "Cell Envelope.1995". http://www.micro.siu.edu/micr425/425Notes/02-CellEnv.html. Retrieved 2008-11-08. 
  7. ^ Woodyer RD, Shao Z, Thomas PM, et al (November 2006). "Heterologous production of fosfomycin and identification of the minimal biosynthetic gene cluster". Chemistry & biology 13 (11): 1171–82. doi:10.1016/j.chembiol.2006.09.007. PMID 17113999. http://linkinghub.elsevier.com/retrieve/pii/S1074-5521(06)00340-1. 
  8. ^ Navas, J; León, J; Arroyo, M; García Lobo, JM (1990). "Nucleotide sequence and intracellular location of the product of the fosfomycin resistance gene from transposon Tn2921". Antimicrobial agents and chemotherapy 34 (10): 2016–8. PMID 1963292.  edit
  9. ^ Kahan, FM; Kahan, JS; Cassidy, PJ; Kropp, H (1974). "The mechanism of action of fosfomycin (phosphonomycin)". Annals of the New York Academy of Sciences 235 (0): 364–86. PMID 4605290.  edit
  10. ^ a b Rigsby, R.; Fillgrove, K.; Beihoffer, L.; Armstrong, R. (2005). "Fosfomycin Resistance Proteins: A Nexus of Glutathione Transferases and Epoxide Hydrolases in a Metalloenzyme Superfamily". Methods in Enzymology 401: 367. doi:10.1016/S0076-6879(05)01023-2.  edit
  11. ^ García P, Arca P, Evaristo Suárez J (July 1995). "Product of fosC, a gene from Pseudomonas syringae, mediates fosfomycin resistance by using ATP as cosubstrate". Antimicrob. Agents Chemother. 39 (7): 1569–73. PMID 7492106.& PMC 162783. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=7492106. 

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