Bacterial cell wall synthesis

Fosfomycin sodium is an antibacterial agent for epoxy. In contrast to other antibacterial drugs, its mechanism of action involves impeding the first stage of cell wall formation [1]. With a 90% inhibition rate, fosfomycin sodium exhibits bactericidal efficacy against a range of Gram-positive and Gram-negative pathogenic bacteria, including β-bacteria that produce carbapenemase and extended-spectrum lactamases[1]. Because of its wide tissue penetration, fosfomycin sodium is useful in the research of infections pertaining to the lungs, soft tissue, bone, central nervous system, and abscesses [2].

In rats, fosfomycin (80 mg/kg; orally or intravenously) protects against double bekacin nephrotoxicity and is unaffected by administration routes [3]. Rats' fosfomycin pharmacokinetics [4] Dibekacin dosage (mg) Vdss (l/kg) β (min-1) T1/2 (min) Urinary recovery rate (%) 30 0.261 0.0244 28.4 85

Fosfomycin is a bactericidal antibiotic agent. It inhibits an enzyme-catalyzed reaction in the first step of the synthesis of the bacterial cell wall. Fosfomycin interferes with the first cytoplasmic step of bacterial cell wall biosynthesis, the formation of the peptidoglycan precursor UDP N-acetylmuramic acid (UDP-MurNAc). Specifically, the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is involved in peptidoglycan biosynthesis by catalyzing the transfer of the enolpyruvyl moiety of phosphoenolpyruvate (PEP) to the 3′-hydroxyl group of UDP-N-acetylglucosamine (UNAG). Fosfomycin covalently binds to the thiol group of a cysteine (position 115 in Escherichia coli numbering; target Cys115) in the active site of MurA and consequently inactivates it. This inhibitory action takes place at an earlier step than the action of β-lactams or glycopeptides [1].

Fosfomycin exerts immunomodulatory effects by altering lymphocyte, monocyte and neutrophil function. It affects the acute inflammatory cytokine response in vitro and in vivo. It suppresses production of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-1α and increases production of IL-10, while contradictory data have been published regarding IL-6. On the other hand, concentrations of TNF-α, IL-1β, and IL-6 expressed as protein and mRNA were almost identical with and without fosfomycin in healthy volunteers. Fosfomycin suppresses IL-2 production from T cells, the production of leukotriene B4 (LTB4) from neutrophils, and the expression of IL-8 mRNA by LTB4 from monocytes. Fosfomycin also exhibits an immunomodulatory effect on B-cell activation. Fosfomycin enhances neutrophil phagocytic killing of invading pathogens, even in patients on chronic hemodialysis and renal transplantation). Fosfomycin resulted in enhanced bactericidal ability of neutrophils compared to other antimicrobials. The clinical relevance of the aforementioned actions remains to be elucidated [1].

Animal/Disease Models: Fischer 344 rats [3]
Doses: 320 mg/kg
Route of Administration: intramuscularinjection, 5 courses of treatment: 1 hour, 0.5 hrs (hrs (hours)) earlier than Dibekacin, at the same time, 0.5 hrs (hrs (hours)) later, later 1 hour; 11 days
Experimental Results: Following previous treatment, polyuria, proteinuria, enzymes and cytosine were diminished due to dibekacin (40 mg/kg).

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Animal/Disease Models: Acute renal failure dehydrated Wistar rats (8 weeks old) [4]
Doses: 120 mg/kg
Route of Administration: intravenous (iv) (iv)injection; 200mg/kg. The first
Experimental Results:the elimination rate of rats basically returned to normal, and the nephrotoxicity parameters improved. Protects proximal tubular lysosomes from the effects of aminoglycosides by inhibiting myelopoiesis and protecting the integrity of lysosomal membranes in rats treated with bibekacin.

Absorption, Distribution and Excretion
Fosfomycin is a low molecular weight hydrophilic drug. After oral administration, fosfomycin is rapidly absorbed in the small intestine and widely distributed in tissues. Oral bioavailability is 34-58%. Co-administration with food reduces its gastrointestinal absorption by approximately 30%. Reported AUC is 145-228 mg·h/L, and Cmax is 26.1 (±9.1) mcg/mL. Fosfomycin is almost completely excreted by the kidneys. Co-administration with food, impaired renal function, and advanced age may reduce fosfomycin clearance. In healthy subjects, the volume of distribution (Vd) of fosfomycin is approximately 0.3 L/kg. Due to changes in vascular endothelial cells, the Vd can increase by up to 50% in critically ill patients. One study reported a clearance/expenditure (CL/F) of 17 ± 4.7 L/h in healthy volunteers after fosfomycin administration.

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Metabolism/Metabolites
Fosfomycin is not metabolized and is mainly excreted unchanged in the urine.

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Biological Half-Life
The mean elimination half-life of fosfomycin is 5.7 (± 2.8) hours.

Hepatotoxicity
Following a single oral dose of fosfomycin, a small percentage (1-2%) of patients may experience elevated serum transaminases, but the incidence is similar to that of other control antibiotics. Nevertheless, the fosfomycin product information still lists elevated serum enzymes as a potential adverse reaction. In addition, a small number of clinically significant cases of fosfomycin-related liver injury have been reported. These cases have a rapid onset, usually within one week after a single oral dose or within the first week after intravenous treatment, and the pattern of liver enzyme elevation is mixed or hepatocellular. Liver injury is usually mild and self-limiting, and there is currently no conclusive evidence that fatal acute liver failure, chronic hepatitis, or bile duct disappearance syndrome is associated with fosfomycin. The number of cases described is too small to establish a typical clinical pattern, but immune hypersensitivity features and autoimmune markers appear to be uncommon. Probability score: D (Possibly a rare cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Limited information suggests that fosfomycin is present in low concentrations in breast milk, and is unlikely to be well absorbed by infants due to its binding with calcium in breast milk. No adverse effects on breastfed infants are likely.
◉ Effects on breastfed infants
No relevant published information found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information found as of the revision date.

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Protein binding
Fosfomycin binds very little to plasma proteins.

[1]. Fosfomycin. Clin Microbiol Rev. 2016 Apr. 29(2):321-47.
[2]. Fosfomycin: Pharmacological, Clinical and Future Perspectives. Antibiotics (Basel). 2017 Oct 31. 6(4):24.
[3]. Mode of protective action of fosfomycin against dibekacin-induced nephrotoxicity in the dehydrated rats. J Pharmacobiodyn. 1982 Dec. 5(12):941-50.

Fosfomycin is a phosphonic acid with a (R,S)-1,2-epoxypropyl group attached to its phosphorus atom. It is an antibacterial agent and an inhibitor of EC 2.5.1.7 (UDP-N-acetylglucosamine 1-carboxyvinyltransferase). It is an epoxide belonging to the phosphonic acid class of compounds. Its function is related to phosphonic acids. It is the conjugate acid of (1R,2S)-epoxypropylphosphonate (1-). Fosfomycin was discovered in 1969 by scientists at the Spanish penicillin and antibiotics company and is produced by Streptomyces fradiae. It can also be synthesized artificially and marketed as a disodium salt (for intravenous injection) and calcium or tromethamine salts (for oral administration). Chemically, fosfomycin is a phosphoenolpyruvate analog containing a phosphonic acid group and an epoxy ring. Due to its single oral dose of 3 grams and good safety profile, fosfomycin has become a first-line treatment option for uncomplicated urinary tract infections in women. Although fosfomycin is only approved by the FDA for the treatment of urinary tract infections, it actually possesses broad-spectrum antibacterial activity, effective against both Gram-positive and Gram-negative bacteria. Therefore, there is considerable interest in exploring its potential applications beyond urinary tract infections. Fosfomycin is an oral broad-spectrum antibiotic primarily used to treat uncomplicated urinary tract infections. Transient elevations in serum enzymes during fosfomycin treatment are rare, but in rare cases, clinically significant acute liver injury with jaundice may occur. Fosfomycin has been reported in Arabidopsis thaliana, Streptomyces wedmore, and several other organisms with relevant data. Fosfomycin is a phosphoenolpyruvate analogue, a synthetic broad-spectrum antibiotic with antibacterial and bactericidal properties. Fosfomycin binds to and inactivates enolpyruvate transferase. This irreversibly inhibits the condensation reaction of uridine diphosphate-N-acetylglucosamine with phosphoenolpyruvate, the first step in bacterial cell wall synthesis, ultimately leading to cell lysis and bacterial death. It is an antibiotic produced by Streptomyces freundii. See also: Fosfomycin Tromethamine (active fraction). Fosfomycin Calcium (active ingredient); Fosfomycin Sodium (active ingredient).

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Drug Indications
Fosfomycin is indicated for the treatment of uncomplicated cystitis caused by susceptible Escherichia coli and Enterococcus faecalis. Fosfomycin is not officially approved for the treatment of pyelonephritis or perirenal abscess, but off-label use in these conditions has been reported.
FDA LabelMechanism of Action
Fosfomycin exerts its bactericidal effect by covalently binding to a cysteine residue at the active site of UDP-N-acetylglucosamine enolpyruvate transferase (MurA), thereby inactivating it. Fosfomycin inhibits the formation of the peptidoglycan precursor UDP-N-acetylmuramic acid (UDP-MurNAc) by preventing MurA from catalyzing the condensation reaction of phosphoenolpyruvate (PEP) with UDP-N-acetylglucosamine (UNAG). Ultimately, the first step in bacterial cell wall synthesis is disrupted. In Escherichia coli, fosfomycin enters bacterial cells through two mechanisms: the L-α-glycerophosphate system and the hexose-6-phosphate transport system. Fosfomycin also has an important effect on cell adhesion. For example, fosfomycin can reduce the adhesion of bacterial cells to urethral epithelial cells. The adhesion of Streptococcus pneumoniae and Haemophilus influenzae to respiratory epithelial cells is also reduced.

C3H7O4P

138.05908

138.008

C, 26.10; H, 5.11; O, 46.35; P, 22.44

23155-02-4

Fosfomycin calcium;26016-98-8;Fosfomycin sodium;26016-99-9;(Rac)-Fosfomycin (benzylamine)-13C3;1216461-18-5

446987

Solid powder

1.561g/cm3

342.651ºC at 760 mmHg

94ºC

161.03ºC

0mmHg at 25°C

1.486

-1.4

2

4

1

8

138

2

C[C@H]1[C@H](O1)P(=O)(O)O

YMDXZJFXQJVXBF-STHAYSLISA-N

InChI=1S/C3H7O4P/c1-2-3(7-2)8(4,5)6/h2-3H,1H3,(H2,4,5,6)/t2-,3+/m0/s1

((2R,3S)-3-methyloxiran-2-yl)phosphonic acid

MK-955; MK 955; MK955; Antibiotic 833A; Fosfonomycin

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: > 10 mM

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)