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==History==
==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.<ref>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.</ref> CEPA began producing fosfomycin on an industrial scale in 1971 at its [[Aranjuez]] facility.<ref>Encros [http://www.ercros.es/eng/internas.asp?arxiu=qh_aranjuezh About us: Our history.]</ref>
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.<ref>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.</ref> CEPA began producing fosfomycin on an industrial scale in 1971 at its [[Aranjuez]] facility.<ref>Encros [http://www.ercros.es/eng/internas.asp?arxiu=qh_aranjuezh About us: Our history.] {{webarchive|url=https://web.archive.org/web/20110914142734/http://www.ercros.es/eng/internas.asp?arxiu=qh_aranjuezh |date=2011-09-14 }}</ref>


==Uses==
==Uses==
Line 80: Line 80:
==Mechanism of action==
==Mechanism of action==


Fosfomycin is bactericidal and inhibits bacterial cell wall biogenesis by inactivating the enzyme [[UDP-N-acetylglucosamine enolpyruvyl transferase|UDP-''N''-acetylglucosamine-3-enolpyruvyltransferase]], also known as MurA.<ref name="Brown">{{cite journal | vauthors = Brown ED, Vivas EI, Walsh CT, Kolter R | title = MurA (MurZ), the enzyme that catalyzes the first committed step in peptidoglycan biosynthesis, is essential in Escherichia coli | journal = Journal of Bacteriology | volume = 177 | issue = 14 | pages = 4194–7 | date = Jul 1995 | pmid = 7608103 | pmc = 177162 }}</ref> This enzyme catalyzes the [[committed step]] in [[peptidoglycan]] biosynthesis, namely the ligation of [[phosphoenolpyruvate]] (PEP) to the 3'-hydroxyl group of [[Uridine diphosphate N-acetylglucosamine|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 [[alkylation|alkylating]] an active site [[cysteine]] residue (Cys 115 in the ''[[Escherichia coli]]'' enzyme).<ref name="urlCell Envelope.1995">{{cite web |url=http://www.micro.siu.edu/micr425/425Notes/02-CellEnv.html |title=Cell Envelope.1995 |work= |accessdate=2008-11-08}}</ref>
Fosfomycin is bactericidal and inhibits bacterial cell wall biogenesis by inactivating the enzyme [[UDP-N-acetylglucosamine enolpyruvyl transferase|UDP-''N''-acetylglucosamine-3-enolpyruvyltransferase]], also known as MurA.<ref name="Brown">{{cite journal | vauthors = Brown ED, Vivas EI, Walsh CT, Kolter R | title = MurA (MurZ), the enzyme that catalyzes the first committed step in peptidoglycan biosynthesis, is essential in Escherichia coli | journal = Journal of Bacteriology | volume = 177 | issue = 14 | pages = 4194–7 | date = Jul 1995 | pmid = 7608103 | pmc = 177162 }}</ref> This enzyme catalyzes the [[committed step]] in [[peptidoglycan]] biosynthesis, namely the ligation of [[phosphoenolpyruvate]] (PEP) to the 3'-hydroxyl group of [[Uridine diphosphate N-acetylglucosamine|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 [[alkylation|alkylating]] an active site [[cysteine]] residue (Cys 115 in the ''[[Escherichia coli]]'' enzyme).<ref name="urlCell Envelope.1995">{{cite web |url=http://www.micro.siu.edu/micr425/425Notes/02-CellEnv.html |title=Cell Envelope.1995 |work= |accessdate=2008-11-08 |deadurl=yes |archiveurl=https://web.archive.org/web/20090330140157/http://www.micro.siu.edu/micr425/425Notes/02-CellEnv.html |archivedate=2009-03-30 |df= }}</ref>


Fosfomycin enters the bacterial cell through the glycerophosphate transporter.<ref name="santoro">{{cite journal | vauthors = Santoro A, Cappello AR, Madeo M, Martello E, Iacopetta D, Dolce V | title = Interaction of fosfomycin with the glycerol 3-phosphate transporter of Escherichia coli. | journal = Biochimica et Biophysica Acta | volume = 1810 | issue = 12 | pages = 1323–1329| date = Jul 2011 | pmid = 21791237| doi =10.1016/j.bbagen.2011.07.006}}</ref>
Fosfomycin enters the bacterial cell through the glycerophosphate transporter.<ref name="santoro">{{cite journal | vauthors = Santoro A, Cappello AR, Madeo M, Martello E, Iacopetta D, Dolce V | title = Interaction of fosfomycin with the glycerol 3-phosphate transporter of Escherichia coli. | journal = Biochimica et Biophysica Acta | volume = 1810 | issue = 12 | pages = 1323–1329| date = Jul 2011 | pmid = 21791237| doi =10.1016/j.bbagen.2011.07.006}}</ref>

Revision as of 18:37, 4 October 2017

Not to be confused with Fosmidomycin.
Fosfomycin
Structural formula of fosfomycin
Ball-and-stick model of the fosfomycin molecule
Clinical data
Trade namesMonurol
AHFS/Drugs.comMonograph
MedlinePlusa697008
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability30–37% (oral, fosfomycin tromethamine); varies with food intake
Protein bindingNil
MetabolismNil
Elimination half-life5.7 hours (mean)
ExcretionRenal and fecal, 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 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 (also known as phosphomycin or phosphonomycin and the trade names Monurol and Monuril) is a broad-spectrum antibiotic[1] produced by certain Streptomyces species, although it can now be made by chemical synthesis.

As a single dose, fosfomycin is more convenient than a multiple-dose therapy norfloxacin, for the same antibacterial efficacy.[2]

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 (UTIs), 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. It is not recommended for children and those over 75 years old.[8]

Additional uses have been proposed.[9] The global problem of advancing antimicrobial resistance has led to a renewed interest in its use more recently.[10]

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.[11] 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).[12]

Fosfomycin enters the bacterial cell through the glycerophosphate transporter.[13]

Antibacterial spectrum and susceptibility

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

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.

Biosynthetic gene cluster

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.[14]

Resistance

Mutations that inactivate the nonessential glycerophosphate transporter render bacteria resistant to fosfomycin.[15][16][17]

Fosfomycin resistance enzymes

Enzymes conferring resistance to fosfomycin have also been identified and are encoded both chromosomally and on plasmids.[18]

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 used in the reaction: glutathione for FosA, bacillithiol for FosB,[19][20] and water for FosX.[18] In general, FosA and FosX enzymes are produced by Gram-negative bacteria, whereas FosB is produced by Gram-positive bacteria.[18]

FosC uses ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective.[21]

References

  1. ^ Grif K, Dierich MP, Pfaller K, Miglioli PA, Allerberger F (Aug 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. ^ de Jong Z1, Pontonnier F, Plante P. "Single-dose fosfomycin trometamol (Monuril) versus multiple-dose norfloxacin: results of a multicenter study in females with uncomplicated lower urinary tract infections". Urol Int. 46: 344–8. doi:10.1159/000282164. PMID 1926651.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  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. Archived 2011-09-14 at the Wayback Machine
  5. ^ a b Patel SS, Balfour JA, Bryson HM (Apr 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, Moorehead L, Montgomery AB, Geller DE (2012). "Fosfomycin/tobramycin for inhalation in patients with cystic fibrosis with pseudomonas airway infection". American Journal of Respiratory and Critical Care Medicine. 185 (2): 171–8. doi:10.1164/rccm.201105-0924OC. PMC 3361752. PMID 22095545.
  7. ^ Clinical trial number NCT00794586 for "Study Evaluating Fosfomycin/Tobramycin for Inhalation in Cystic Fibrosis Patients With Pseudomonas Aeruginosa Lung Infection" at ClinicalTrials.gov
  8. ^ "MONURIL SACHETS 3G". Retrieved May 26, 2014.
  9. ^ Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI (Apr 2008). "Fosfomycin: use beyond urinary tract and gastrointestinal infections". Clinical Infectious Diseases. 46 (7): 1069–77. doi:10.1086/527442. PMID 18444827.
  10. ^ Falagas ME, Grammatikos AP, Michalopoulos A (Oct 2008). "Potential of old-generation antibiotics to address current need for new antibiotics". Expert Review of Anti-Infective Therapy. 6 (5): 593–600. doi:10.1586/14787210.6.5.593. PMID 18847400.
  11. ^ Brown ED, Vivas EI, Walsh CT, Kolter R (Jul 1995). "MurA (MurZ), the enzyme that catalyzes the first committed step in peptidoglycan biosynthesis, is essential in Escherichia coli". Journal of Bacteriology. 177 (14): 4194–7. PMC 177162. PMID 7608103.
  12. ^ "Cell Envelope.1995". Archived from the original on 2009-03-30. Retrieved 2008-11-08. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  13. ^ Santoro A, Cappello AR, Madeo M, Martello E, Iacopetta D, Dolce V (Jul 2011). "Interaction of fosfomycin with the glycerol 3-phosphate transporter of Escherichia coli". Biochimica et Biophysica Acta. 1810 (12): 1323–1329. doi:10.1016/j.bbagen.2011.07.006. PMID 21791237.
  14. ^ Woodyer RD, Shao Z, Thomas PM, Kelleher NL, Blodgett JA, Metcalf WW, van der Donk WA, Zhao H (Nov 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.
  15. ^ Navas J, León J, Arroyo M, García Lobo JM (1990). "Nucleotide sequence and intracellular location of the product of the fosfomycin resistance gene from transposon Tn2921". Antimicrobial Agents and Chemotherapy. 34 (10): 2016–8. doi:10.1128/AAC.34.10.2016. PMC 171982. PMID 1963292.
  16. ^ Kahan FM, Kahan JS, Cassidy PJ, Kropp H (1974). "The mechanism of action of fosfomycin (phosphonomycin)". Annals of the New York Academy of Sciences. 235: 364–86. Bibcode:1974NYASA.235..364K. doi:10.1111/j.1749-6632.1974.tb43277.x. PMID 4605290.
  17. ^ Castañeda-García A, Blázquez J, Rodríguez-Rojas A (2013). "Molecular Mechanisms and Clinical Impact of Acquired and Intrinsic Fosfomycin Resistance". Antibiotics. 2 (2): 217–36. doi:10.3390/antibiotics2020217. PMC 4790336. PMID 27029300.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ a b c Rigsby RE, Fillgrove KL, Beihoffer LA, Armstrong RN (2005). "Fosfomycin resistance proteins: a nexus of glutathione transferases and epoxide hydrolases in a metalloenzyme superfamily". Methods in Enzymology. Methods in Enzymology. 401: 367–379. doi:10.1016/S0076-6879(05)01023-2. ISBN 9780121828066. PMID 16399398. {{cite journal}}: |chapter= ignored (help)
  19. ^ Sharma SV, Jothivasan VK, Newton GL, Upton H, Wakabayashi JI, Kane MG, Roberts AA, Rawat M, La Clair JJ, Hamilton CJ (Jul 2011). "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. doi:10.1002/anie.201100196. PMID 21751306.
  20. ^ Roberts AA, Sharma SV, Strankman AW, Duran SR, Rawat M, Hamilton CJ (Apr 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.
  21. ^ García P, Arca P, Evaristo Suárez J (Jul 1995). "Product of fosC, a gene from Pseudomonas syringae, mediates fosfomycin resistance by using ATP as cosubstrate". Antimicrobial Agents and Chemotherapy. 39 (7): 1569–73. doi:10.1128/aac.39.7.1569. PMC 162783. PMID 7492106.
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