Fosfomycin

Not to be confused with Fosmidomycin.

Fosfomycin

Systematic (IUPAC) name
[(2R,3S)-3-methyloxiran-2-yl]phosphonic acid
Clinical data
Trade names	Monurol
AHFS/Drugs.com	monograph
MedlinePlus	a697008
Pregnancy cat.	B(US)
Legal status	℞-only (US)
Routes	Oral
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
Identifiers
CAS number	23155-02-4 78964-85-9
ATC code	J01XX01
PubChem	CID 446987
DrugBank	APRD00987
ChemSpider	394204 Y
UNII	2N81MY12TE Y
KEGG	D04253 Y
ChEBI	CHEBI:28915 Y
ChEMBL	CHEMBL1757 Y
Chemical data
Formula	C3H7O4P
Mol. mass	138.059 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C3H7O4P/c1-2-3(7-2)8(4,5)6/h2-3H,1H3,(H2,4,5,6)/t2-,3+/m0/s1 Y Key:YMDXZJFXQJVXBF-STHAYSLISA-N Y
Y(what is this?)  (verify)

Fosfomycin (also known as phosphomycin and phosphonomycin) (trade names Monurol, Monuril) is a broad-spectrum antibiotic^[1] produced by certain Streptomyces species.

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 inhibits bacterial cell wall biogenesis by inactivating the enzyme UDP-N-acetylglucosamine-3-enolpyruvyltransferase, also known as MurA.^[5] 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).^[6]

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 utilized in the reaction: 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]

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. doi:10.1093/jac/48.2.209. PMID 11481290. http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11481290. 
2. ^ ^{a b} Patel SS, Balfour JA, Bryson HM (1997). "Fosfomycin tromethamine: A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections". Drugs 53 (4): 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. PMC 177162. PMID 7608103. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=177162. 
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, J. M. (1990). "Nucleotide sequence and intracellular location of the product of the fosfomycin resistance gene from transposon Tn2921". Antimicrobial agents and chemotherapy 34 (10): 2016–2018. PMC 171982. PMID 1963292. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=171982.  edit
9. ^ Kahan, F. M.; Kahan, J. S.; Cassidy, P. J.; Kropp, H. (1974). "The mechanism of action of fosfomycin (phosphonomycin)". Annals of the New York Academy of Sciences 235 (0): 364–386. Bibcode 1974NYASA.235..364K. doi:10.1111/j.1749-6632.1974.tb43277.x. 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. "Gluthione Transferases and Gamma-Glutamyl Transpeptidases". Methods in Enzymology. Methods in Enzymology 401: 367–379. doi:10.1016/S0076-6879(05)01023-2. ISBN 9780121828066. PMID 16399398.  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. PMC 162783. PMID 7492106. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=7492106. 

External links

• Fosfomycin information at RxList