Structure-Guided Development of ClpP Agonists with Potent Therapeutic Activities against <i>Staphylococcus aureus</i> Infection
Tao Zhang, Wei Wu, Yanling Zhao, Ziang Ding, Bingyan Wei, Teng Yang, Jiahui Li, Pengyu Wang, Lefu Lan, Jianhua Gan, Cai‐Guang Yang
Abstract
Peritonitis caused by Staphylococcus aureus poses a severe threat to patients with end-stage renal failure. Treating multidrug-resistant S. aureus infections requires the use of antibiotics with diverse mechanisms of action. Caseinolytic protease P (ClpP) is a promising antibacterial target; however, selective activation of S. aureus ClpP ( Sa ClpP) over human ClpP ( Hs ClpP) remains challenging. We previously identified ( R )-ZG197 as a selective Sa ClpP agonist, but its potency was suboptimal. Herein, we develop ( R )-ZG197 analogs through a structure-guided approach and examine their structure–activity relationships. Notably, ZY39 demonstrates improved activation of Sa ClpP and superior binding affinity. Interestingly, while ZY39 facilitates the enzymatic hydrolysis of Sa ClpP and Hs ClpP in vitro, it does not target Hs ClpP in cellular environments. Furthermore, ZY39 effectively inhibits the growth of multidrug-resistant S. aureus strains and shows excellent therapeutic efficacy in a murine model of peritonitis. These findings highlight ZY39 as a promising Sa ClpP agonist for combating staphylococcal infections.