ClyJ Is a Novel Pneumococcal Chimeric Lysin with a Cysteine- and Histidine-Dependent Amidohydrolase/Peptidase Catalytic Domain
ClyJ Is a Novel Pneumococcal Chimeric Lysin with a Cysteine- and Histidine-Dependent Amidohydrolase/Peptidase Catalytic Domain
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ClyJ 是一种新型肺炎球菌嵌合溶素，具有半胱氨酸和组氨酸依赖性酰胺水解酶/肽酶催化结构域
DOI：
10.1128/aac.02043-18
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发表时间：
2019
影响因子：
4.9
通讯作者：
Wei Hongping
中科院分区：
文献类型：
--
作者：
Yang Hang;Gong Yujing;Zhang Huaidong;Etobayeva Irina;Miernikiewicz Paulina;Luo Dehua;Li Xiaohong;Zhang Xiaoxu;Dabrowska Krystyna;Nelson Daniel C.;He Jin;Wei Hongping
肺炎链球菌是引起多种粘膜和侵袭性感染的主要病原体之一。随着多药耐药链球菌的出现，肺炎，迫切需要具有不同于常规抗生素的作用机制的新的抗微生物剂。摘要肺炎链球菌是引起多种粘膜和侵袭性感染的主要病原体之一。随着多药耐药链球菌的出现，肺炎，迫切需要具有不同于常规抗生素的作用机制的新的抗微生物剂。在这项研究中，我们确定了一个假定的溶素（gp 20）编码的链球菌噬菌体SPSL 1使用LytA自溶素作为模板。gp 20的分子解剖揭示了一个结合结构域（GPB），其中含有对S.肺炎。通过将GPB融合到PlyC溶素的半胱氨酸、组氨酸依赖性酰胺水解酶/肽酶（cysteine，histidine-dependent amidohydrolase/peptidase）催化结构域，我们构建了一种新的嵌合溶素ClyJ，其对肺炎球菌Cpl-1溶素具有改善的活性。S.在体外暴露于递增加倍浓度的ClyJ连续8天后，在使用青霉素G作为对照的小鼠菌血症模型中，单次腹腔注射ClyJ提高了致死性S.肺炎克雷伯氏菌感染的小鼠以剂量依赖性方式。鉴于其高溶解活性和安全性，ClyJ可能是对抗肺炎球菌感染的一种有希望的替代方案。
Streptococcus pneumoniae is one of the leading pathogens that cause a variety of mucosal and invasive infections. With the increased emergence of multidrug-resistant S. pneumoniae, new antimicrobials with mechanisms of action different from conventional antibiotics are urgently needed. ABSTRACT Streptococcus pneumoniae is one of the leading pathogens that cause a variety of mucosal and invasive infections. With the increased emergence of multidrug-resistant S. pneumoniae, new antimicrobials with mechanisms of action different from conventional antibiotics are urgently needed. In this study, we identified a putative lysin (gp20) encoded by the Streptococcus phage SPSL1 using the LytA autolysin as a template. Molecular dissection of gp20 revealed a binding domain (GPB) containing choline-binding repeats (CBRs) that are high specificity for S. pneumoniae. By fusing GPB to the CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) catalytic domain of the PlyC lysin, we constructed a novel chimeric lysin, ClyJ, with improved activity to the pneumococcal Cpl-1 lysin. No resistance was observed in S. pneumoniae strains after exposure to incrementally doubling concentrations of ClyJ for 8 continuous days in vitro. In a mouse bacteremia model using penicillin G as a control, a single intraperitoneal injection of ClyJ improved the survival rate of lethal S. pneumoniae-infected mice in a dose-dependent manner. Given its high lytic activity and safety profile, ClyJ may represent a promising alternative to combat pneumococcal infections.