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

Peritonitis caused by poses a severe threat to patients with end-stage renal failure. Treating multidrug-resistant infections requires the use of antibiotics with diverse mechanisms of action. Caseinolytic protease P (ClpP) is a promising antibacterial target; however, selective activation of (ClpP) over human ClpP (ClpP) remains challenging. We previously identified as a selective ClpP agonist, but its potency was suboptimal. Herein, we develop analogs through a structure-guided approach and examine their structure-activity relationships. Notably, demonstrates improved activation of ClpP and superior binding affinity. Interestingly, while facilitates the enzymatic hydrolysis of ClpP and ClpP , it does not target ClpP in cellular environments. Furthermore, effectively inhibits the growth of multidrug-resistant strains and shows excellent therapeutic efficacy in a murine model of peritonitis. These findings highlight as a promising ClpP agonist for combating staphylococcal infections.