Pharmacokinetics and Pharmacodynamics of Fungal Defensin NZX Against Staphylococcus aureus-Induced Mouse Peritonitis Model

文献类型： 外文期刊

第一作者： Zheng, Xueling

作者： Zheng, Xueling;Yang, Na;Mao, Ruoyu;Hao, Ya;Teng, Da;Wang, Jianhua;Zheng, Xueling;Yang, Na;Mao, Ruoyu;Hao, Ya;Teng, Da;Wang, Jianhua;Zheng, Xueling;Yang, Na;Mao, Ruoyu;Hao, Ya;Teng, Da;Wang, Jianhua

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关键词： fungal defensin NZX; Staphylococcus aureus; intracellular bactericidal activity; pharmacokinetics; pharmacodynamics; mouse peritonitis model

期刊名称：FRONTIERS IN MICROBIOLOGY （ 影响因子：6.064； 五年影响因子：6.843 ）

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年卷期： 2022 年 13 卷

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收录情况： SCI

摘要： Staphylococcus aureus (S. aureus) is one of the most common pathogenic bacteria responsible for causing a life-threatening peritonitis disease. NZX, as a variant of fungal defensin plectasin, displayed potent antibacterial activity against S. aureus. In this study, the antibacterial and resistance characteristics, pharmacokinetics, and pharmacodynamics of NZX against the S. aureus E48 and S. aureus E48-induced mouse peritonitis model were studied, respectively. NZX exhibited a more rapid killing activity to S. aureus (minimal inhibitory concentration, 1 mu g/ml) compared with linezolid, ampicillin and daptomycin, and serial passaging of S. aureus E48 for 30 days at 1/2 x MIC, NZX had a lower risk of resistance compared with ampicillin and daptomycin. Also, it displayed a high biocompatibility and tolerance to physiological salt, serum environment, and phagolysosome proteinase environment, except for acid environment in phagolysosome. The murine serum protein-binding rate of NZX was 89.25% measured by ultrafiltration method. Based on the free NZX concentration in serum after tail vein administration, the main pharmacokinetic parameters for T-1/2, C-max, V-d, MRT, and AUC ranged from 0.32 to 0.45 h, 2.85 to 20.55 mu g/ml, 1469.10 to 2073.90 ml/kg, 0.32 to 0.56 h, and 1.11 to 8.89 mu g.h/ml, respectively. Additionally, the in vivo pharmacodynamics against S. aureus demonstrated that NZX administrated two times by tail vein at 20 mg/kg could rescue all infected mice in the lethal mouse peritonitis model. And NZX treatment (20 mg/kg) significantly reduced CFU counts in the liver, lung, and spleen, especially for intracellular bacteria in the peritoneal fluid, which were similar or superior to those of daptomycin. In vivo efficacies of NZX against total bacteria and intracellular bacteria were significantly correlated with three PK/PD indices of integral AUC/MIC, integral C-max/MIC, and integral T% > MIC analyzed by a sigmoid maximum-effect model. These results showed that NZX may be a potential candidate for treating peritonitis disease caused by intracellular S. aureus.

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