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Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

文献类型：期刊论文

作者Wei, Bingyan2,3,4; Zhang, Tao3; Wang, Pengyu2,3,4; Pan, Yihui2,3,4; Li, Jiahui3,4; Chen, Weizhong5; Zhang, Min1; Ji, Quanjiang5; Wu, Wenjuan1; Lan, Lefu2,3,4
刊名NATURE COMMUNICATIONS
出版日期2022-11-14
卷号13期号:1页码:16
DOI10.1038/s41467-022-34753-0
通讯作者Yang, Cai-Guang(yangcg@simm.ac.cn)
英文摘要The development of selective ClpP activators targeting only the MRSA isolates without interfering with the human variant is currently challenging. Here, the authors report on the structure-based design of enantiomers of ZG197 and identify the discriminator factor between the proteins. The emergence of methicillin-resistant Staphylococcus aureus isolates highlights the urgent need to develop more antibiotics. ClpP is a highly conserved protease regulated by ATPases in bacteria and in mitochondria. Aberrant activation of bacterial ClpP is an alternative method of discovering antibiotics, while it remains difficult to develop selective Staphylococcus aureus ClpP activators that can avoid disturbing Homo sapiens ClpP functions. Here, we use a structure-based design to identify (R)- and (S)-ZG197 as highly selective Staphylococcus aureus ClpP activators. The key structural elements in Homo sapiens ClpP, particularly W146 and its joint action with the C-terminal motif, significantly contribute to the discrimination of the activators. Our selective activators display wide antibiotic properties towards an array of multidrug-resistant staphylococcal strains in vitro, and demonstrate promising antibiotic efficacy in zebrafish and murine skin infection models. Our findings indicate that the species-specific activators of Staphylococcus aureus ClpP are exciting therapeutic agents to treat staphylococcal infections.
WOS关键词SMALL-MOLECULE ACTIVATORS ; ACYLDEPSIPEPTIDE ANALOGS ; PROTEASE ; VIRULENCE ; INHIBITOR ; CRYSTALLOGRAPHY ; DYSREGULATION ; MODULATORS ; RESISTANCE ; TOLERANCE
资助项目National Natural Science Foundation of China[22037007] ; National Natural Science Foundation of China[81861138046] ; National Natural Science Foundation of China[21725801] ; National Natural Science Foundation of China[22107109]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:000883836600017
源URL[http://119.78.100.183/handle/2S10ELR8/304578]  
专题新药研究国家重点实验室
通讯作者Yang, Cai-Guang
作者单位1.Tongji Univ, Shanghai East Hosp, Dept Lab Med, Sch Med, Shanghai 200123, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
3.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Ctr Chem Biol, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China
6.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
推荐引用方式
GB/T 7714		 Wei, Bingyan,Zhang, Tao,Wang, Pengyu,et al. Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP[J]. NATURE COMMUNICATIONS,2022,13(1):16.
APA Wei, Bingyan.,Zhang, Tao.,Wang, Pengyu.,Pan, Yihui.,Li, Jiahui.,...&Yang, Cai-Guang.(2022).Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP.NATURE COMMUNICATIONS,13(1),16.
MLA Wei, Bingyan,et al."Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP".NATURE COMMUNICATIONS 13.1(2022):16.

入库方式： OAI收割

来源：上海药物研究所

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