Discovery of SaClpP-Selective Imipridone Derivatives as Novel Antistaphylococcal Agents

Based on ONC212, a previously reported activator of hClpP and SaClpP, a novel class of SaClpP-selective imipridones featuring a substituted group at C8 was designed, synthesized, and evaluated. Among them, the representative compound 26 activated hClpP and SaClpP with EC₅₀ values of 19.7 and 0.98 μM, respectively. Consistent with its weak enzymatic activity on hClpP, compound 26 exhibited over 100-fold lower toxicity than ONC212 in the HEK293FT, MIAPACA2, and SW480 cell lines. Notably, compound 26 demonstrated potent antibacterial activity against a panel of Staphylococcus aureus strains, including hospital-acquired multidrug-resistant MRSA, with minimum inhibitory concentration values ranging from 0.25 to 1 μg/mL. Furthermore, it effectively promoted wound healing in a murine skin infection model using S. aureus American Type Culture Collection 25923. These findings underscore its promising therapeutic potential, along with its analogues, for the treatment of S. aureus infections.