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Fosfomycin

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Not to be confused with Fosmidomycin.

Fosfomycin
Structural formula of fosfomycin
Ball-and-stick model of the fosfomycin molecule
Clinical data
Trade namesMonuril, Monurol, Ivozfo, others
Other namesPhosphomycin, phosphonomycin, fosfomycin tromethamine
AHFS/Drugs.comMonograph
MedlinePlusa697008
License data
Routes of
administration		Intravenous, By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability30–37% (by mouth, fosfomycin tromethamine); varies with food intake
Protein bindingNil
MetabolismNil
Elimination half-life5.7 hours (mean)
ExcretionKidney, unchanged
Identifiers
  • [(2R,3S)-3-methyloxiran-2-yl]phosphonic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.041.315 Edit this at Wikidata
Chemical and physical data
FormulaC3H7O4P
Molar mass138.059 g·mol−1
3D model (JSmol)
Melting point94 °C (201 °F)
  • C[C@H]1[C@H](O1)P(=O)(O)O
  • InChI=1S/C3H7O4P/c1-2-3(7-2)8(4,5)6/h2-3H,1H3,(H2,4,5,6)/t2-,3+/m0/s1 checkY
  • Key:YMDXZJFXQJVXBF-STHAYSLISA-N checkY
  (verify)

Fosfomycin, sold under the brand name Monurol among others, is an antibiotic primarily used to treat lower urinary tract infections.[8] It is not indicated for kidney infections.[8] Occasionally it is used for prostate infections.[8] It is generally taken by mouth.[8]

Common side effects include diarrhea, nausea, headache, and vaginal yeast infections.[8] Severe side effects may include anaphylaxis and Clostridioides difficile-associated diarrhea.[8] While use during pregnancy has not been found to be harmful, such use is not recommended.[9] A single dose when breastfeeding appears safe.[9] Fosfomycin works by interfering with the production of the bacterial cell wall.[8]

Fosfomycin was discovered in 1969 and approved for medical use in the United States in 1996 [globalize][8][10] It is on the World Health Organization's List of Essential Medicines.[11] The World Health Organization classifies fosfomycin as critically important for human medicine.[12] It is available as a generic medication.[13] It was originally produced by certain types of Streptomyces, although it is now made chemically.[10]

Medical uses

[edit]

Fosfomycin is used to treat bladder infections as well as urinary tract infections (UTIs), where it is usually given as a single dose by mouth.[14]

Oral fosfomycin is not recommended for children under 12 years old.[15]

Additional uses have been proposed.[16] The global problem of advancing antimicrobial resistance has led to a renewed interest in its use more recently.[17]

Fosfomycin can be used as an efficacious treatment for both UTIs and complicated UTIs including acute pyelonephritis. The standard regimen for complicated UTIs is an oral 3 g dose administered once every 48 or 72 hours for a total of 3 doses or a 6 g dose every 8 hours for 7–14 days when fosfomycin is given in IV form.[18]

Intravenous fosfomycin is being increasingly used for treating infections caused by multidrug-resistant bacteria, mostly as a partner drug in order to avoid the occurrence of resistances and to take advantage of its synergistic activity with several other antimicrobials. Daily adult dose usually ranges from 12 to 24 grams.[19] When administered in continuous infusion, a loading dose of fosfomycin 8 g followed by a daily dose of 16 g or 24 g. Continuous infusion is suggested in patients with normal renal function.[20]

Bacterial sensitivity

[edit]

The fosfomycin molecule has an epoxide or oxirane ring, which is highly strained and thus very reactive.[citation needed]

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 such as 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 UTIs caused by these uropathogens. Of note, activity against S. saprophyticus, Klebsiella, and Enterobacter is variable and should be confirmed by minimum inhibitory concentration testing. Activity against extended-spectrum β-lactamase-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 UTIs, caused by susceptible organisms. However, susceptibility break-points of 64 mg/L should not be applied for systemic infections.[citation needed]

Resistance

[edit]

Development of bacterial resistance under therapy is a frequent occurrence and makes fosfomycin unsuitable for sustained therapy of severe infections. Mutations that inactivate the nonessential glycerophosphate transporter render bacteria resistant to fosfomycin.[21][22][23] Still, fosfomycin can be used to treat MRSA bacteremia.[24]

Prescribing fosfomycin together with at least another active drug reduces the risk of developing bacterial resistance. Fosfomycin acts synergistically with many other antibiotics, including aminoglycosides, carbapenems, cephalosporins, daptomycin and oritavancin.[19][25]

Enzymes conferring resistance to fosfomycin have also been identified and are encoded both chromosomally and on plasmids.[26]

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.[citation needed]

The enzymes differ by the identity of the nucleophile used in the reaction: glutathione for FosA, bacillithiol for FosB,[27][28] and water for FosX.[26]

In general, FosA and FosX enzymes are produced by Gram-negative bacteria, whereas FosB is produced by Gram-positive bacteria.[26]

FosC uses ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective.[29]

Side effects

[edit]

The drug is well tolerated and has a low incidence of harmful side effects.[14]

Mechanism of action

[edit]

Despite its name (ending in -omycin) Fosfomycin is not a macrolide, but a member of a novel class of phosphonic antibiotics. Fosfomycin is bactericidal and inhibits bacterial cell wall biogenesis by inactivating the enzyme UDP-N-acetylglucosamine-3-enolpyruvyltransferase, also known as MurA.[30] 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).[31][32]

Fosfomycin enters the bacterial cell through the glycerophosphate transporter.[33]

History

[edit]

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.[34] CEPA began producing fosfomycin on an industrial scale in 1971 at its Aranjuez facility.[35]

Biosynthesis

[edit]

The complete fosfomycin biosynthetic gene cluster from Streptomyces fradiae has been cloned and sequenced and the heterologous production of fosfomycin in S. lividans has been achieved by Ryan Woodyer of the Huimin Zhao and Wilfred van der Donk research groups.[36]

Synthetic manufacture

[edit]

Large scale production of fosfomycin is achieved by making an epoxide of cis-propenylphosphonic acid to yield racemic mixture fosfomycin.[37]

References

[edit]
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  28. ^ Roberts AA, Sharma SV, Strankman AW, Duran SR, Rawat M, Hamilton CJ (April 2013). "Mechanistic studies of FosB: a divalent-metal-dependent bacillithiol-S-transferase that mediates fosfomycin resistance in Staphylococcus aureus". The Biochemical Journal. 451 (1): 69–79. doi:10.1042/BJ20121541. PMC 3960972. PMID 23256780.
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  30. ^ 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". Journal of Bacteriology. 177 (14): 4194–4197. doi:10.1128/jb.177.14.4194-4197.1995. PMC 177162. PMID 7608103.
  31. ^ Zhu JY, Yang Y, Han H, Betzi S, Olesen SH, Marsilio F, Schönbrunn E (April 2012). "Functional consequence of covalent reaction of phosphoenolpyruvate with UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA)". The Journal of Biological Chemistry. 287 (16): 12657–12667. doi:10.1074/jbc.M112.342725. PMC 3339971. PMID 22378791.
  32. ^ Krekel F, Samland AK, Macheroux P, Amrhein N, Evans JN (October 2000). "Determination of the pKa value of C115 in MurA (UDP-N-acetylglucosamine enolpyruvyltransferase) from Enterobacter cloacae". Biochemistry. 39 (41): 12671–12677. doi:10.1021/bi001310x. PMID 11027147.
  33. ^ Santoro A, Cappello AR, Madeo M, Martello E, Iacopetta D, Dolce V (December 2011). "Interaction of fosfomycin with the glycerol 3-phosphate transporter of Escherichia coli". Biochimica et Biophysica Acta (BBA) - General Subjects. 1810 (12): 1323–1329. doi:10.1016/j.bbagen.2011.07.006. PMID 21791237.
  34. ^ Silver LL (2011). "Rational Approaches to Antibacterial Discovery: Pre-Genomic Directed and Phenotypic Screening". In Dougherty T, Pucci MJ (eds.). Antibiotic Discovery and Development. Springer. p. 46. doi:10.1007/978-1-4614-1400-1_2. ISBN 978-1-4614-1400-1.
  35. ^ "About us: Our history". Encros. Archived from the original on 14 September 2011.
  36. ^ Woodyer RD, Shao Z, Thomas PM, Kelleher NL, Blodgett JA, Metcalf WW, et al. (November 2006). "Heterologous production of fosfomycin and identification of the minimal biosynthetic gene cluster". Chemistry & Biology. 13 (11): 1171–1182. doi:10.1016/j.chembiol.2006.09.007. PMID 17113999.
  37. ^ Marocco CP, Davis EV, Finnell JE, Nguyen PH, Mateer SC, Ghiviriga I, et al. (2011). "Asymmetric synthesis of (−)-fosfomycin and its trans-(1S,2S)-diastereomer using a biocatalytic reduction as the key step". Tetrahedron: Asymmetry. 22 (18–19). Elsevier BV: 1784–1789. doi:10.1016/j.tetasy.2011.10.009. ISSN 0957-4166.
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