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.