Fosfomycin

Not to be confused with Fosmidomycin.

Fosfomycin

Structural formula of fosfomycin
Ball-and-stick model of the fosfomycin molecule
Systematic (IUPAC) name
[(2R,3S)-3-methyloxiran-2-yl]phosphonic acid
Clinical data
Trade names	Monurol
AHFS/Drugs.com	monograph
MedlinePlus	a697008
Pregnancy category	US: B (No risk in non-human studies)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	30–37% (oral, fosfomycin tromethamine); varies with food intake
Protein binding	Nil
Metabolism	Nil
Biological half-life	5.7 hours (mean)
Excretion	Renal and fecal, unchanged
Identifiers
CAS Number	23155-02-4 Y Template:CAS
ATC code	J01XX01 (WHO)
PubChem	CID: 446987
DrugBank	DB00828 Y
ChemSpider	394204 Y
UNII	2N81MY12TE Y
KEGG	D04253 Y
ChEBI	CHEBI:28915 Y
ChEMBL	CHEMBL1757 Y
Chemical data
Formula	C3H7O4P
Molecular mass	138.059 g/mol
SMILES C[C@H]1[C@H](O1)P(=O)(O)O
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
Physical data
Melting point	94 °C (201 °F)
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Fosfomycin (also known as phosphomycin, phosphonomycin and the trade name Monurol and Monuril) is a broad-spectrum antibiotic produced by certain Streptomyces species, although it can now be made by chemical synthesis.

History

Fosfomycin (originally known as phosphonomycin) was discovered in a joint effort of Merck and Co. and Spain's 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.

Uses

Fosfomycin is indicated in the treatment of urinary tract infections, where it is usually administered as a single oral megadose. Its use in combination with tobramycin to treat lung infections in patients with cystic fibrosis was also explored.

The drug is well tolerated and has a low incidence of harmful side-effects. However, development of bacterial resistance under therapy is a frequent occurrence and makes fosfomycin unsuitable for sustained therapy of severe infections. It is not recommended for children and those over 75 years old.

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

Mechanism of action

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.

Antibacterial spectrum and susceptibility

Fosfomycin has broad antibacterial activity against both Gram-positive and Gram-negative pathogens, with useful activity against E. faecalis, E. coli, and various Gram-negatives like Citrobacter and Proteus. Given a greater activity in a low pH milieu, and predominant excretion in active form into the urine, fosfomycin has found use for the prophylaxis and treatment of urinary tract infections caused by these uropathogens. Of note, activity against S. saprophyticus, Klebsiella and Enterobacter is variable and should be confirmed by minimum inhibitory concentration (MIC) testing. Activity against extended-spectrum β-lactamase (ESBL)-producing pathogens, notably ESBL-producing E. coli is good to excellent, because the drug is not affected by cross-resistance issues. Existing clinical data support use in uncomplicated UTI, caused by susceptible organisms. However, susceptibility break-points of 64 mg/L should not be applied for systemic infections.

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.

Resistance

Mutations that inactivate the non-essential glycerophosphate transporter render bacteria resistant to fosfomycin.

Fosfomycin resistance enzymes

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 utilized 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 utilizes ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective.

External links

• Fosfomycin information at RxList