Details of the Drug

General Information of Drug (ID: DMVGPMX)

• Drug Name: Fosfomycin
• Synonyms: FCM; Phosphomycin; Phosphonemycin; Phosphonomycin; Priomicina; Veramina; Disodium fosfomycin; Disodium phosphonomycin; Fosfocina disodium salt; Fosfomycin disodium; Fosfomycin disodium salt; Fosfomycin sodium; Fosfomycin sodium salt; Fosmicin S; Phosphomycin disodium salt; Phosphonomycin disodium salt; Phosphonomycin sodium; Sodium fosfomycin; MK 955; FOM-Na; Fosfomycin sodium (JP15); Fosmicin S (TN); Fosfomycin (USAN/INN); L-cis-1,2-epoxypropylphosphonic acid; Disodium (1R,2S)-(1,2-epoxypropyl)phosphonate; Disodium[(2r,3s)-3-methyloxiran-2-yl]phosphonate; [(2R,3S)-3-methyloxiran-2-yl]phosphonic acid; Phosphonic acid, (3-methyloxiranyl)-, disodium salt, (2R-cis)-(9CI); (-)-(1R,2S)-(1,2-Epoxypropyl)phosphonicacid; (1R,2S)(-)-(1,2-Epoxypropyl)phosphonic acid disodium salt; (1R,2S)-(1,2-Epoxypropyl)phosphonic acid; (1R,2S)-epoxypropylphosphonate; (1R,2S)-epoxypropylphosphonic acid; (2R-cis)-(3-Methyloxiranyl)phosphonic acid disodium salt

Indication

Disease Entry	ICD 11	Status	REF
Bacterial infection	1A00-1C4Z	Approved	[1]

• Therapeutic Class: Antibiotics
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 138.06
  Topological Polar Surface Area (xlogp); -1.4
  Rotatable Bond Count (rotbonds); 1
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 4
• ADMET Property:
  Absorption Tmax: The time to maximum plasma concentration (Tmax) is 1.5 h [2]
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [3]
  Bioavailability: The bioavailability of drug is 55% [2]
  Clearance: The clearance of drug is 17 +/- 4.7 L/h [4]
  Elimination: 82% of drug is excreted from urine in the unchanged form [3]
  Half-life: The concentration or amount of drug in body reduced by one-half in 5.7 (?2.8) hours [5]
  Metabolism: The drug is not metabolised [6]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 192.901 micromolar/kg/day [7]
  Unbound Fraction: The unbound fraction of drug in plasma is 1% [8]
  Vd: The volume of distribution (Vd) of drug is 0.3 L/kg [6]
  Water Solubility: The ability of drug to dissolve in water is measured as 50 mg/mL [3]
• Chemical Identifiers:
  Formula: C3H7O4P
  IUPAC Name: [(2R,3S)-3-methyloxiran-2-yl]phosphonic acid
  Canonical SMILES: C[C@H]1[C@H](O1)P(=O)(O)O
  InChI: InChI=1S/C3H7O4P/c1-2-3(7-2)8(4,5)6/h2-3H,1H3,(H2,4,5,6)/t2-,3+/m0/s1
  InChIKey: YMDXZJFXQJVXBF-STHAYSLISA-N
• Cross-matching ID:
  PubChem CID: 446987
  ChEBI ID: CHEBI:28915
  CAS Number: 23155-02-4
  DrugBank ID: DB00828
  TTD ID: D01GYT
  INTEDE ID: DR0749

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Bacterial UDP-N-acetylglucosamine carboxyvinyltransferase (Bact murA)	TTICX3S	MURA_ECOLI	Inhibitor	[9], [10], [11], [12]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Glutathione S-transferase alpha-1 (GSTA1) Main DME	DE4ZHS1	GSTA1_HUMAN	Substrate	[13]

References

• [1] Has nature already identified all useful antibacterial targets Curr Opin Microbiol. 2008 Oct;11(5):387-92.
• [2] Wen YG, Shang DW, Xie HZ, Wang XP, Ni XJ, Zhang M, Lu W, Qiu C, Liu X, Li FF, Li X, Luo FT: Population pharmacokinetics of blonanserin in Chinese healthy volunteers and the effect of the food intake. Hum Psychopharmacol. 2013 Mar;28(2):134-41. doi: 10.1002/hup.2290. Epub 2013 Feb 18.
• [3] BDDCS applied to over 900 drugs
• [4] Wenzler E, Ellis-Grosse EJ, Rodvold KA: Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers. Antimicrob Agents Chemother. 2017 Aug 24;61(9). pii: AAC.00775-17. doi: 10.1128/AAC.00775-17. Print 2017 Sep.
• [5] FDA Approved Drug Products: Monurol (fosfomycin tromethamine)
• [6] Elroby SA, Makki MS, Sobahi TR, Hilal RH: Toward the understanding of the metabolism of levodopa I. DFT investigation of the equilibrium geometries, acid-base properties and levodopa-water complexes. Int J Mol Sci. 2012;13(4):4321-39. doi: 10.3390/ijms13044321. Epub 2012 Apr 2.
• [7] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [8] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [9] Evidence that the fosfomycin target Cys115 in UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is essential for product release. J Biol Chem. 2005 Feb 4;280(5):3757-63.
• [10] Conditional lethal amber mutations in essential Escherichia coli genes. J Bacteriol. 2004 May;186(9):2673-81.
• [11] In vitro and in vivo functional activity of Chlamydia MurA, a UDP-N-acetylglucosamine enolpyruvyl transferase involved in peptidoglycan synthesis and fosfomycin resistance. J Bacteriol. 2003 Feb;185(4):1218-28.
• [12] Lysine 22 in UDP-N-acetylglucosamine enolpyruvyl transferase from Enterobacter cloacae is crucial for enzymatic activity and the formation of covalent adducts with the substrate phosphoenolpyruvate and the antibiotic fosfomycin. Biochemistry. 1999 Oct 5;38(40):13162-9.
• [13] Formation of an adduct between fosfomycin and glutathione: a new mechanism of antibiotic resistance in bacteria. Antimicrob Agents Chemother. 1988 Oct;32(10):1552-6.
• [14] Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin. Mol Cancer Ther. 2008 Oct;7(10):3247-55.
• [15] Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. J Biol Chem. 2001 Aug 31;276(35):33061-5.
• [16] Retinoid X receptor alpha regulates the expression of glutathione s-transferase genes and modulates acetaminophen-glutathione conjugation in mouse liver. Mol Pharmacol. 2005 Dec;68(6):1590-6.
• [17] Comparison of basal glutathione S-transferase activities and of the influence of phenobarbital, butylated hydroxy-anisole or 5,5'-diphenylhydantoin on enzyme activity in male rodents. Comp Biochem Physiol C. 1987;88(1):91-3.
• [18] Characterization and formation of the glutathione conjugate of clofibric acid. Drug Metab Dispos. 1995 Jan;23(1):119-23.
• [19] In vitro characterization of the human biotransformation and CYP reaction phenotype of ET-743 (Yondelis, Trabectidin), a novel marine anti-cancer drug. Invest New Drugs. 2006 Jan;24(1):3-14.
• [20] Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004 Sep 1;104(5):1574-7.
• [21] Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer. 2002 Feb 10;97(5):700-5.
• [22] Purification and biochemical properties of glutathione S-transferase from Lactuca sativa. J Biochem Mol Biol. 2005 Mar 31;38(2):232-7.
• [23] Combined glutathione-S-transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity. Clin Pharmacol Ther. 2000 Apr;67(4):432-7.
• [24] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [25] Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98.
• [26] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [27] Sesquiterpene lactones are potent and irreversible inhibitors of the antibacterial target enzyme MurA. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5605-9.