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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Inhibition of Fosfomycin Resistance Protein FosA by Phosphonoformate (Foscarnet) in Multidrug-Resistant Gram-Negative Pathogens
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Inhibition of Fosfomycin Resistance Protein FosA by Phosphonoformate (Foscarnet) in Multidrug-Resistant Gram-Negative Pathogens

机译：通过磷酸族血管霉素（FOSCARNET）在多药抗革兰阴性病原体中的抑制抑制FOSFOMYCIN抗性蛋白FOSA

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摘要

FosA proteins confer fosfomycin resistance to Gram-negative pathogens via glutathione-mediated modification of the antibiotic. In this study, we assessed whether inhibition of FosA by sodium phosphonoformate (PPF) (foscarnet), a clinically approved antiviral agent, would reverse fosfomycin resistance in representative Gram-negative pathogens. The inhibitory activity of PPF against purified recombinant FosA from Escherichia coli (FosA3), Klebsiella pneumoniae (FosA(KP)), Enterobacter cloacae (FosA(EC)), and Pseudomonas aeruginosa (FosA(PA)) was determined by steadystate kinetic measurements. The antibacterial activity of PPF against FosA in clinical strains of these species was evaluated by susceptibility testing and time-kill assays. PPF increased the Michaelis constant (K-m) for fosfomycin in a dose-dependent manner, without affecting the maximum rate (V-max) of the reaction, for all four FosA enzymes tested, indicating a competitive mechanism of inhibition. Inhibitory constant (K-i) values were 22.6, 35.8, 24.4, and 56.3 mu M for FosA(KP), FosA(EC), FosA(PA), and FosA3, respectively. Addition of clinically achievable concentrations of PPF (similar to 667 mu M) reduced the fosfomycin MICs by >= 4-fold among 52% of the K. pneumoniae, E. cloacae, and P. aeruginosa clinical strains tested and led to a bacteriostatic or bactericidal effect in time-kill assays among representative strains. PPF inhibits FosA activity across Gram-negative species and can potentiate fosfomycin activity against the majority of strains with chromosomally encoded fosA. These data suggest that PPF may be repurposed as an adjuvant for fosfomycin to treat infections caused by some FosAproducing, multidrug-resistant, Gram-negative pathogens.
机译：FOSA蛋白通过谷胱甘肽介导的抗生素的改性赋予素霉素抗革兰阴性病原体。在这项研究中，我们评估了磷酸钠（PPF）（Foscarnet），临床批准的抗病毒剂的抑制抑制剂，将逆转代表性革兰氏阴性病原体中的氟霉素抗性。通过EstequenceState动力学测量测定PPF来自大肠杆菌（FOSA3），肠杆菌菌（FOSA（kP）），肠杆菌（FOSA（eCO））和假单胞菌（FOSA（PA））测定来自大肠杆菌（FOSA3），Klebsiella肺炎（FOSA（kp））和假单胞菌动力学测量。通过易感性测试和时间杀死测定评估PPF对这些物种临床菌株中FOSA的抗菌活性。 PPF以剂量依赖性方式增加咪霉素的Michaelis常数（K-M），而不会影响反应的最大速率（V-Max），对于测试的所有四种FOSA酶，表明抑制竞争机制。对于FOSA（KP），FOSA（EC），FOSA（PA）和FOSA3，抑制常数（K-1）值分别为22.6,35.8,24.4和56.3μm。添加临床上可实现的PPF浓度（类似于667μm）将FOSFOMYCIN MICS在52％的K.PNEUMONIAE，E.Cloacea和P.铜绿假单胞临床菌株中的52％中降低> = 4倍并导致抑菌或代表性菌株中时滞测定的杀菌作用。 PPF抑制革兰阴性物种的福斯菌，并且可以使染色体编码的FOSA大多数菌株能够使FOSFOMYCIN活性提高。这些数据表明，PPF可以作为福斯福霉素作为佐剂重新施用，以治疗由一些粘接剂，多药，革兰氏阴性病原体引起的感染。

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