Structure-Guided Development of ClpP Agonists with Potent Therapeutic Activities against Staphylococcus aureus Infection

Tao Zhang; Wei Wu; Yanling Zhao; Ziang Ding; Bingyan Wei; Teng Yang; Jiahui Li; Pengyu Wang; Lefu Lan; Jianhua Gan; Cai-Guang Yang

doi:10.1021/acs.jmedchem.4c02562

Structure-Guided Development of ClpP Agonists with Potent Therapeutic Activities against Staphylococcus aureus Infection

J Med Chem. 2025 Jan 6. doi: 10.1021/acs.jmedchem.4c02562. Online ahead of print.

Authors

Tao Zhang¹, Wei Wu^{1

2}, Yanling Zhao³, Ziang Ding³, Bingyan Wei⁴, Teng Yang⁴, Jiahui Li^{1

2}, Pengyu Wang⁴, Lefu Lan^{4

2}, Jianhua Gan⁵, Cai-Guang Yang^{1

3

4

2

6}

Affiliations

¹ State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
⁴ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
⁵ School of Life Sciences, Fudan University, Shanghai 200433, China.
⁶ Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.

PMID: 39760203
DOI: 10.1021/acs.jmedchem.4c02562

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 (SaClpP) over human ClpP (HsClpP) remains challenging. We previously identified (R)-ZG197 as a selective SaClpP 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 SaClpP and superior binding affinity. Interestingly, while ZY39 facilitates the enzymatic hydrolysis of SaClpP and HsClpP in vitro, it does not target HsClpP 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 SaClpP agonist for combating staphylococcal infections.