Fosfomycin sodium, a phosphoenolpyruvate (PEP) analog, is a powerful and orally active antibiotic that inhibits Escherichia coli MurA Enzyme with IC50 value of 8.8μmol/L[1]. Fosfomycin sodium covalently modifies the thiol of a cysteine (position 115 in Escherichia coli numbering; target Cys115) in the active site of MurA and thereby inactivates the enzyme[2]. Fosfomycin sodium has been employed in antibacterial and immunoregulatory assays[3].
In vitro, Fosfomycin sodium was active against 88.6% of the extended spectrum ß-lactamases (ESBLs)-producing E. coli ESBL strains and the MIC values (16h) for most of the strains were ≤16mg/L. The MIC50 and MIC90 were 1 and 32mg/L, respectively, for 16h[4]. Treatment of HEK293 human embryonic kidney cells with Fosfomycin sodium for 24h significantly inhibited cell viability with the IC50 values of 41.4μg/ml[5]. Fosfomycin sodium treatment (200μg/ml, 48h) significantly inhibited proliferation of Human peripheral blood mononuclear cells, accompanied by the reduced IL-2 levels[6].
In vivo, Fosfomycin sodium at a dose of 320mg/kg/day (12 days, intramuscular injection) has a significant protective effect on experimental nephrotoxicity induced by dibekacin (40mg/kg/day, intramuscular injection) in male Fischer 344 rats, resulting in improvement of renal histopathology and ultrastructure, and reduction of blood urea nitrogen and creatinine levels in rats[7]. Intravenous administration of Fosfomycin sodium at a dose of 120mg/kg/day significantly improved acute renal failure induced by 30mg/kg dibekacin (Intravenous injection), inhibited myeloid formation and protected lysosomal membrane integrity in Male Wistar SPF rats[8].
References:
[1] Baum E Z, Montenegro D A, Licata L, et al. Identification and characterization of new inhibitors of the Escherichia coli MurA enzyme[J]. Antimicrobial agents and chemotherapy, 2001, 45(11): 3182-3188.
[2] Falagas M E, Vouloumanou E K, Samonis G, et al. Fosfomycin[J]. Clinical microbiology reviews, 2016, 29(2): 321-347.
[3] Silver L L. Fosfomycin: mechanism and resistance[J]. Cold Spring Harbor perspectives in medicine, 2017, 7(2): a025262.
[4] Aprile A, Scalia G, Stefani S, et al. In vitro fosfomycin study on concordance of susceptibility testing methods against ESBL and carbapenem-resistant Enterobacteriaceae[J]. Journal of Global Antimicrobial Resistance, 2020, 23: 286-289.
[5]Khazaal M T, Faraag A H I, El-Hendawy H H. In vitro and in silico studies of enterobactin-inspired Ciprofloxacin and Fosfomycin first generation conjugates on the antibiotic resistant E. coli OQ866153[J]. BMC microbiology, 2024, 24(1): 95.
[6] Morikawa K, Oseko F, Morikawa S, et al. Immunosuppressive activity of fosfomycin on human T-lymphocyte function in vitro[J]. Antimicrobial agents and chemotherapy, 1993, 37(12): 2684-2687.
[7] INOUYE S, NIIZATO T, TAKEDA U, et al. Protective effect of fosfomycin on the experimental nephrotoxicity induced by dibekacin[J]. Journal of pharmacobio-dynamics, 1982, 5(9): 659-669.
[8] INOUYE S, NIIZATO T, KOMIYA I, et al. Mode of protective action of fosfomycin against dibekacin-induced nephrotoxicity in the dehydrated rats[J]. Journal of pharmacobio-dynamics, 1982, 5(12): 941-950.
Fosfomycin sodium是一种磷酸烯醇丙酮酸（PEP）类似物，作为强效口服抗生素，可通过抑制大肠杆菌MurA酶发挥抗菌作用，IC50值为8.8μmol/L[1]。Fosfomycin sodium通过共价修饰MurA酶活性位点的半胱氨酸残基（在大肠杆菌中为Cys115位点）的巯基，从而使MurA酶失活[2]。Fosfomycin sodium已被广泛应用于抗菌试验和免疫调节研究[3]。
在体外，Fosfomycin sodium在对产超广谱β-内酰胺酶（ESBL）的大肠杆菌表现出显著的抗菌活性，抑制率达88.6%，对大多数菌株在16小时内的MIC ≤16mg/L，其中MIC50和MIC90分别为1mg/L和32mg/L[4]。Fosfomycin sodium处理24小时后显著抑制人胚胎肾细胞HEK293的细胞活性，IC50值为41.4μg/ml[5]。Fosfomycin sodium处理（200μg/ml，48小时）能显著抑制人外周血单个核细胞的增殖，并降低IL-2的分泌水平[6]。
在体内，Fosfomycin sodium处理（320mg/kg/day，肌肉注射，12天）对地贝卡星（40mg/kg/day，肌肉注射）诱导的雄性Fischer 344大鼠肾毒性具有显著保护作用，可改善肾脏组织病理学变化和超微结构，并降低血尿素氮和肌酐水平[7]。在雄性Wistar SPF大鼠中，静脉注射Fosfomycin sodium（120mg/kg/day）能有效缓解地贝卡星（30mg/kg，静脉注射）引起的急性肾衰竭，抑制髓样结构形成并保护溶酶体膜完整性[7]。