Fosfomycin

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Not to be confused with Fosmidomycin.
Fosfomycin
FosfomycinImage.svg
Systematic (IUPAC) name
[(2R,3S)-3-methyloxiran-2-yl]phosphonic acid
Clinical data
Trade names Monurol
AHFS/Drugs.com monograph
MedlinePlus a697008
Pregnancy cat.
Legal status
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 YesY 78964-85-9
ATC code J01XX01
PubChem CID 446987
DrugBank DB00828
ChemSpider 394204 YesY
UNII 2N81MY12TE YesY
KEGG D04253 YesY
ChEBI CHEBI:28915 YesY
ChEMBL CHEMBL1757 YesY
Chemical data
Formula C3H7O4P 
Mol. mass 138.059 g/mol
Physical data
Melt. point 94 °C (201 °F)
 YesY (what is this?)  

Fosfomycin (also known as phosphomycin, phosphonomycin and the trade name Monurol and Monuril) is a broad-spectrum antibiotic[1] produced by certain Streptomyces species. Fosfomycin is not recommended for children and 75 up of age.[2] 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.[3] Cepa began producing fosfomycin on an industrial scale in 1971 at its Aranjuez facility.[4]

Uses

Fosfomycin is indicated in the treatment of urinary tract infections, where it is usually administered as a single oral megadose.[5] Its use in combination with tobramycin to treat lung infections in patients with cystic fibrosis was also explored.[6][7]

The drug is well tolerated and has a low incidence of harmful side-effects.[5] 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.[8] The global problem of advancing antimicrobial resistance has led to a renewed interest in its use more recently.[9]

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.[10] 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).[11]

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 MIC testing. Activity against ESBL-producing pathogens, notably ESBL-producing E. coli is good to excellent, due to the fact that 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.[12]

Resistance

Mutations that inactivate the non-essential glycerophosphate transporter render bacteria resistant to fosfomycin.[13][14]

Fosfomycin resistance enzymes

Enzymes conferring resistance to fosfomycin have also been identified and are encoded both chromosomally and on plasmids.[15]

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,[16] [17] and water for FosX.[15] In general, FosA and FosX enzymes are produced by Gram-negative bacteria, whereas FosB is produced by Gram-positive bacteria.[15]

FosC utilizes ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective.[18]

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. 
  2. ^ "MONURIL SACHETS 3G". Retrieved May 26, 2014. 
  3. ^ Silver, L.L. Rational approaches to antibiotic discovery: pre-genomic directed and phenotypic screening, 2.4.2 Screens for spheroplast formation. In: Thomas Dougherty, Michael J. Pucci, Antibiotic Discovery and Development. Chap. 2, p. 46.
  4. ^ Encros About us: Our history.
  5. ^ 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. doi:10.2165/00003495-199753040-00007. PMID 9098664. 
  6. ^ Trapnell BC, McColley SA, Kissner DG, Rolfe MW, Rosen JM, McKevitt M et al. (2011). "Fosfomycin/Tobramycin for Inhalation in Cystic Fibrosis Patients with Pseudomonas Airway Infection.". Am J Respir Crit Care Med 185 (2): 171–8. doi:10.1164/rccm.201105-0924OC. PMID 22095545. 
  7. ^ "Study Evaluating Fosfomycin/Tobramycin for Inhalation in Cystic Fibrosis Patients With Pseudomonas Aeruginosa Lung Infection". US National Library of Medicine. Retrieved 3 May 2012. 
  8. ^ 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. 
  9. ^ 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
  10. ^ 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. 
  11. ^ "Cell Envelope.1995". Retrieved 2008-11-08. 
  12. ^ 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. 
  13. ^ 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. doi:10.1128/AAC.34.10.2016. PMC 171982. PMID 1963292. 
  14. ^ 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. 
  15. ^ a b c 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. 
  16. ^ S. V. Sharma, V. K. Jothivasan, G. L. Newton, H. Upton, J. I.Wakabayashi, M. G. Kane, A. A. Roberts, M. Rawat, J. J. La Clair, and C. J. Hamilton. (July 2011). "Chemical and Chemoenzymatic Syntheses of Bacillithiol: A Unique Low-Molecular-Weight Thiol amongst Low G + C Gram-Positive Bacteria". Angew. Chem. Int. Ed. 50 (31): 7101–7104. doi:10.1002/anie.201100196. PMID 21751306. 
  17. ^ A. A. Roberts, S. V. Sharma, A. W. Strankman, S. R. Duran, M. Rawat, and C. J. Hamilton. (July 2013). "Mechanistic studies of FosB: a divalent-metal-dependent bacillithiol-S-transferase that mediates fosfomycin resistance in Staphylococcus aureus". Biochem. J. 451 (1): 69–79. doi:10.1042/BJ20121541. PMID 23256780. 
  18. ^ 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. doi:10.1128/aac.39.7.1569. PMC 162783. PMID 7492106. 

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