Fri . 19 Apr 2019

Fosfomycin

fosfomycin, fosfomycin antibiotic
Fosfomycin also known as phosphomycin or phosphonomycin and the trade names Monurol and Monuril is a broad-spectrum antibiotic 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

Contents

  • 1 History
  • 2 Uses
  • 3 Mechanism of action
  • 4 Antibacterial spectrum and susceptibility
  • 5 Biosynthetic gene cluster
  • 6 Resistance
    • 61 Fosfomycin resistance enzymes
  • 7 References
  • 8 External links

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 UTIs, 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

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

Resistance

Mutations that inactivate the nonessential 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 used 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 uses ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective

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:101093/jac/482209 PMID 11481290 
  2. ^ de Jong Z, Pontonnier F, Plante P 1991 "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 4: 344–8 doi:101159/000282164 PMID 1926651 
  3. ^ Silver, LL Rational approaches to antibiotic discovery: pre-genomic directed and phenotypic screening, 242 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:102165/00003495-199753040-00007 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:101164/rccm201105-0924OC 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 ClinicalTrialsgov
  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:101086/527442 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:101586/1478721065593 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 Envelope1995" Archived from the original on 2009-03-30 Retrieved 2008-11-08 
  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:101016/jbbagen201107006 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:101016/jchembiol200609007 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:101128/AAC34102016 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:1974NYASA235364K doi:101111/j1749-66321974tb43277x 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:103390/antibiotics2020217 PMC 4790336  PMID 27029300 
  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:101016/S0076-68790501023-2 ISBN 9780121828066 PMID 16399398 
  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:101002/anie201100196 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:101042/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:101128/aac3971569 PMC 162783  PMID 7492106 

External links

  • Fosfomycin information at RxList

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Fosfomycin


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    29.10.2014


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