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

Bingyan Wei, Tao Zhang, Pengyu Wang, Yihui Pan, Jiahui Li, Weizhong Chen, Min Zhang, Quanjiang Ji, Wenjuan Wu, Lefu Lan, Jianhua Gan and Cai-Guang Yang ()
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Bingyan Wei: University of Chinese Academy of Sciences
Tao Zhang: Chinese Academy of Sciences
Pengyu Wang: University of Chinese Academy of Sciences
Yihui Pan: University of Chinese Academy of Sciences
Jiahui Li: Chinese Academy of Sciences
Weizhong Chen: ShanghaiTech University
Min Zhang: Tongji University School of Medicine
Quanjiang Ji: ShanghaiTech University
Wenjuan Wu: Tongji University School of Medicine
Lefu Lan: University of Chinese Academy of Sciences
Jianhua Gan: Fudan University
Cai-Guang Yang: University of Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34753-0

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