A Highly Active Chimeric Lysin with a Calcium-Enhanced Bactericidal Activity against Staphylococcus aureus In Vitro and In Vivo.
A Highly Active Chimeric Lysin with a Calcium-Enhanced Bactericidal Activity against Staphylococcus aureus In Vitro and In Vivo.
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一种高活性嵌合溶素，具有钙增强的体外和体内金黄色葡萄球菌杀菌活性
DOI：
10.3390/antibiotics10040461
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发表时间：
2021-04-19
期刊：
影响因子：
--
通讯作者：
Wei H
中科院分区：
文献类型：
--
作者：
Li X;Wang S;Nyaruaba R;Liu H;Yang H;Wei H
溶菌素，包括嵌合溶菌素，最近被探索作为治疗耐多药（MDR）病原体（包括耐甲氧西林金黄色葡萄球菌（MRSA））失败的抗生素的新的有希望的替代品。本文通过融合Ply187溶酶的CHAP（半胱氨酸，组氨酸依赖的氨基水解酶/肽酶）催化结构域和LysSA97溶酶的非sh3b细胞壁结合结构域，构建了一种新的嵌合溶酶ClyC，其具有Ca2+增强的杀菌活性，可抵抗所有金黄色葡萄球菌菌株，包括MRSA。值得注意的是，在100 μM Ca2+存在下，用50 μg/mL的ClyC处理金黄色葡萄球菌，可使活菌数量减少9 Log10 (CFU/mL)，这是首次观察到溶酶具有如此高的活性。此外，与0.3 μg/mL青霉素g联合使用可使小鼠体内的有效浓度从12 μg/mL显著降低至1 μg/mL。在金黄色葡萄球菌菌血症小鼠模型中，单次腹腔注射0.1 mg/ mL的ClyC可显著提高小鼠的存活率，降低感染小鼠脏器内细菌负荷2 Log10 （CFU/mL）。在没有冷冻保护剂的情况下，冻干后的ClyC也很稳定。基于上述观察结果，ClyC可能是抗金黄色葡萄球菌感染的有希望的候选物。
Lysins, including chimeric lysins, have recently been explored as novel promising alternatives to failing antibiotics in treating multi-drug resistant (MDR) pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Herein, by fusing the CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) catalytic domain from the Ply187 lysin with the non-SH3b cell-wall binding domain from the LysSA97 lysin, a new chimeric lysin ClyC was constructed with Ca2+-enhanced bactericidal activity against all S. aureus strains tested, including MRSA. Notably, treating S. aureus with 50 μg/mL of ClyC in the presence of 100 μM Ca2+ lead to a reduction of 9 Log10 (CFU/mL) in viable bacterial number, which was the first time to observe a lysin showing such a high activity. In addition, the effective concentration of ClyC could be decreased dramatically from 12 to 1 μg/mL by combination with 0.3 μg/mL of penicillin G. In a mouse model of S. aureus bacteremia, a single intraperitoneal administration of 0.1 mg/mouse of ClyC significantly improved the survival rates and reduced 2 Log10 (CFU/mL) of the bacterial burdens in the organs of the infected mice. ClyC was also found stable after lyophilization without cryoprotectants. Based on the above observations, ClyC could be a promising candidate against S. aureus infections.
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