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.