Design and pharmacodynamics of recombinant NZ2114 histidine mutants with improved activity against methicillin-resistant Staphylococcus aureus

文献类型： 外文期刊

第一作者： Chen, Huixian

作者： Chen, Huixian;Feng, Xingjun;Chen, Huixian;Mao, Ruoyu;Teng, Da;Wang, Xiumin;Hao, Ya;Wang, Jianhua;Chen, Huixian;Mao, Ruoyu;Teng, Da;Wang, Xiumin;Hao, Ya;Wang, Jianhua

作者机构：

关键词： Antimicrobial peptide;NZ2114;Pharmacodynamics;Staphylococcus aureus

期刊名称：AMB EXPRESS （ 影响因子：3.298； 五年影响因子：3.427 ）

ISSN： 2191-0855

年卷期： 2017 年 7 卷

页码：

收录情况： SCI

摘要： NZ2114 is a promising candidate for therapeutic application owing to its potent activity to Staphylococcus aureus. Our objective was to identify NZ2114 derivatives with improved activity through substitution of His16 and His18 with residues Arginine and Lysine. Eight mutants were designed and expressed in Pichia pastoris X-33 via pPICZaA. Five of them exhibited strong antimicrobial activity against S. aureus at low minimal inhibitory concentrations (MICs) of 0.057-0.454 mu M. Among them, H1, H2, and H3 showed ideal pharmacodynamic effects on methicillin-resistant S. aureus ATCC43300. The total protein level of H1, H2, and H3 reached 1.70, 1.77 and 1.54 g/l at 120 h of induction in the 5-l fermenter, respectively. They killed over 99.9% of pathogens within 1.5 h at 2x and 4x MIC. The post antibiotic effect of H1, H2 and H3 to S. aureus ATCC43300 was 2.94, 1.75 and 1.55 h at 2x MIC, which was similar with their original peptide NZ2114 (1.43 h) and vancomycin (1.72 h). The fractional inhibitory concentration index (FICI) indicated indifferent effects between H1, H2, H3 and vancomycin, ampicillin, rifampicin. Additionally, they had low hemolysis and high stability in different environments (temperature, pH, proteases, and saline ions). All results indicate that H1, H2, and H3 can be produced in large-scale and have potential as therapeutic drugs against MRSA.

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