Chemistry:Fosfomycin

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Short description: Chemical compound
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC3H7O4P
Molar mass138.059 g·mol−1
3D model (JSmol)
Melting point94 °C (201 °F)
  (verify)

Fosfomycin, sold under the brand name Monurol among others, is an antibiotic primarily used to treat lower urinary tract infections.[6] It is not indicated for kidney infections.[6] Occasionally it is used for prostate infections.[6] It is generally taken by mouth.[6]

Common side effects include diarrhea, nausea, headache, and vaginal yeast infections.[6] Severe side effects may include anaphylaxis and Clostridioides difficile-associated diarrhea.[6] While use during pregnancy has not been found to be harmful, such use is not recommended.[7] A single dose when breastfeeding appears safe.[7] Fosfomycin works by interfering with the production of the bacterial cell wall.[6]

Fosfomycin was discovered in 1969 and approved for medical use in the United States in 1996 Template:Globalize inline.[6][8] It is on the World Health Organization's List of Essential Medicines.[9] The World Health Organization classifies fosfomycin as critically important for human medicine.[10] It is available as a generic medication.[11] It was originally produced by certain types of Streptomyces, although it is now made chemically.[8]

Medical uses

Fosfomycin is used to treat bladder infections, where it is usually given as a single dose by mouth.[12]

Oral fosfomycin is not recommended for children under 12 years old.[13]

Additional uses have been proposed.[14] The global problem of advancing antimicrobial resistance has led to a renewed interest in its use more recently.[15]

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.[16]

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.[17] 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.[18]

Bacterial sensitivity

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

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.[19][20][21]

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.[17][22]

Enzymes conferring resistance to fosfomycin have also been identified and are encoded both chromosomally and on plasmids.[23]

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,[24][25] and water for FosX.[23]

In general, FosA and FosX enzymes are produced by Gram-negative bacteria, whereas FosB is produced by Gram-positive bacteria.[23]

FosC uses ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective.[26]

Side effects

The drug is well tolerated and has a low incidence of harmful side effects.[12]

Mechanism of action

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.[27] 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).[28][29]

Fosfomycin enters the bacterial cell through the glycerophosphate transporter.[30]

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.[31] CEPA began producing fosfomycin on an industrial scale in 1971 at its Aranjuez facility.[32]

Manufacture

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.[33]

Large scale production of fosfomycin is achieved by making an epoxide of cis-propenylphosphonic acid to yield racemic mixture fosfomycin.[34]

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2017". 21 June 2022. https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-chemical-entities-australia-2017. 
  2. ↑ "Regulatory Decision Summary - Ivozfo". 23 October 2014. https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00585. 
  3. ↑ "Monuril 3g granules for oral solution - Summary of Product Characteristics (SmPC)". 1 June 2021. https://www.medicines.org.uk/emc/product/7329. 
  4. ↑ "Fomicyt 40 mg/mL powder for solution for infusion - Summary of Product Characteristics (SmPC)". 11 February 2021. https://www.medicines.org.uk/emc/product/11249/smpc. 
  5. ↑ "Monurol- fosfomycin tromethamine powder". 24 October 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ad155d62-9b49-4a50-a2ae-d3aad8155936. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "Fosfomycin Tromethamine Monograph for Professionals" (in en). https://www.drugs.com/monograph/fosfomycin-tromethamine.html. 
  7. ↑ 7.0 7.1 "Fosfomycin (Monurol) Use During Pregnancy" (in en). https://www.drugs.com/pregnancy/fosfomycin.html. 
  8. ↑ 8.0 8.1 (in en) Antibiotic and Chemotherapy E-Book. Elsevier Health Sciences. 2010. p. 259. ISBN 9780702047657. https://books.google.com/books?id=DE4Mxc3aesEC&pg=PA259. 
  9. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  10. ↑ Critically important antimicrobials for human medicine (6th revision ed.). Geneva: World Health Organization. 2019. ISBN 9789241515528. 
  11. ↑ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 560–561. ISBN 9780857113382. 
  12. ↑ 12.0 12.1 "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. April 1997. doi:10.2165/00003495-199753040-00007. PMID 9098664. 
  13. ↑ "MONURIL SACHETS 3G". https://www.drugs.com/uk/monuril-sachets-3g-leaflet.html. 
  14. ↑ "Fosfomycin: use beyond urinary tract and gastrointestinal infections". Clinical Infectious Diseases 46 (7): 1069–1077. April 2008. doi:10.1086/527442. PMID 18444827. 
  15. ↑ "Potential of old-generation antibiotics to address current need for new antibiotics". Expert Review of Anti-Infective Therapy 6 (5): 593–600. October 2008. doi:10.1586/14787210.6.5.593. PMID 18847400. 
  16. ↑ "Oral and Intravenous Fosfomycin for the Treatment of Complicated Urinary Tract Infections". The Canadian Journal of Infectious Diseases & Medical Microbiology (Hindawi Limited) 2020: 8513405. 2020-03-28. doi:10.1155/2020/8513405. PMID 32300381. 
  17. ↑ 17.0 17.1 "Fosfomycin as Partner Drug for Systemic Infection Management. A Systematic Review of Its Synergistic Properties from In Vitro and In Vivo Studies". Antibiotics 9 (8): 500. August 2020. doi:10.3390/antibiotics9080500. PMID 32785114. 
  18. ↑ "Fosfomycin in continuous or prolonged infusion for systemic bacterial infections: a systematic review of its dosing regimen proposal from in vitro, in vivo and clinical studies". European Journal of Clinical Microbiology & Infectious Diseases 40 (6): 1117–1126. June 2021. doi:10.1007/s10096-021-04181-x. PMID 33604721. 
  19. ↑ "Nucleotide sequence and intracellular location of the product of the fosfomycin resistance gene from transposon Tn2921". Antimicrobial Agents and Chemotherapy 34 (10): 2016–2018. October 1990. doi:10.1128/AAC.34.10.2016. PMID 1963292. 
  20. ↑ "The mechanism of action of fosfomycin (phosphonomycin)". Annals of the New York Academy of Sciences 235 (1): 364–386. May 1974. doi:10.1111/j.1749-6632.1974.tb43277.x. PMID 4605290. Bibcode: 1974NYASA.235..364K. 
  21. ↑ "Molecular Mechanisms and Clinical Impact of Acquired and Intrinsic Fosfomycin Resistance". Antibiotics 2 (2): 217–236. April 2013. doi:10.3390/antibiotics2020217. PMID 27029300. 
  22. ↑ "In Vitro and In Vivo Studies of Oritavancin and Fosfomycin Synergism against Vancomycin-Resistant Enterococcus faecium". Antibiotics 11 (10): 1334. September 2022. doi:10.3390/antibiotics11101334. PMID 36289992. 
  23. ↑ 23.0 23.1 23.2 "Fosfomycin resistance proteins: a nexus of glutathione transferases and epoxide hydrolases in a metalloenzyme superfamily". Gluthione [sic] Transferases and Gamma-Glutamyl Transpeptidases. Methods in Enzymology. 401. 2005. pp. 367–379. doi:10.1016/S0076-6879(05)01023-2. ISBN 9780121828066. https://archive.org/details/gluthionetransfe00sies/page/367. 
  24. ↑ "Chemical and Chemoenzymatic syntheses of bacillithiol: a unique low-molecular-weight thiol amongst low G + C Gram-positive bacteria". Angewandte Chemie 50 (31): 7101–7104. July 2011. doi:10.1002/anie.201100196. PMID 21751306. 
  25. ↑ "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. April 2013. doi:10.1042/BJ20121541. PMID 23256780. 
  26. ↑ "Product of fosC, a gene from Pseudomonas syringae, mediates fosfomycin resistance by using ATP as cosubstrate". Antimicrobial Agents and Chemotherapy 39 (7): 1569–1573. July 1995. doi:10.1128/aac.39.7.1569. PMID 7492106. 
  27. ↑ "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. July 1995. doi:10.1128/jb.177.14.4194-4197.1995. PMID 7608103. 
  28. ↑ "Functional consequence of covalent reaction of phosphoenolpyruvate with UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA)". The Journal of Biological Chemistry 287 (16): 12657–12667. April 2012. doi:10.1074/jbc.M112.342725. PMID 22378791. 
  29. ↑ "Determination of the pKa value of C115 in MurA (UDP-N-acetylglucosamine enolpyruvyltransferase) from Enterobacter cloacae". Biochemistry 39 (41): 12671–12677. October 2000. doi:10.1021/bi001310x. PMID 11027147. 
  30. ↑ "Interaction of fosfomycin with the glycerol 3-phosphate transporter of Escherichia coli". Biochimica et Biophysica Acta (BBA) - General Subjects 1810 (12): 1323–1329. December 2011. doi:10.1016/j.bbagen.2011.07.006. PMID 21791237. 
  31. ↑ "Rational Approaches to Antibacterial Discovery: Pre-Genomic Directed and Phenotypic Screening". Antibiotic Discovery and Development. Springer. 2011. pp. 46. doi:10.1007/978-1-4614-1400-1_2. ISBN 978-1-4614-1400-1. 
  32. ↑ "About us: Our history". Encros. http://www.ercros.es/eng/internas.asp?arxiu=qh_aranjuezh. 
  33. ↑ "Heterologous production of fosfomycin and identification of the minimal biosynthetic gene cluster". Chemistry & Biology 13 (11): 1171–1182. November 2006. doi:10.1016/j.chembiol.2006.09.007. PMID 17113999. 
  34. ↑ "Asymmetric synthesis of (−)-fosfomycin and its trans-(1S,2S)-diastereomer using a biocatalytic reduction as the key step". Tetrahedron: Asymmetry (Elsevier BV) 22 (18–19): 1784–1789. 2011. doi:10.1016/j.tetasy.2011.10.009. ISSN 0957-4166. 

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