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.

本研究以既往报道的人源ClpP（human mitochondrial ClpP, hClpP）与金黄色葡萄球菌ClpP（Staphylococcus aureus ClpP, SaClpP）激活剂ONC212为母核，设计、合成并评价了一类在C8位引入取代基团的新型SaClpP选择性伊米吡酮（imipridones）类衍生物。其中代表性化合物26对hClpP与SaClpP均具有激活活性，半数有效浓度（median effective concentration, EC50）分别为19.7 μM与0.98 μM。与其对hClpP较弱的酶促活性相符，化合物26在HEK293FT、MIAPACA2及SW480细胞系中的细胞毒性较ONC212低100倍以上。值得注意的是，化合物26对一系列金黄色葡萄球菌（Staphylococcus aureus）菌株展现出强效抗菌活性，涵盖医院获得性多重耐药耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus, MRSA），其最低抑菌浓度（minimum inhibitory concentration, MIC）范围为0.25~1 μg/mL。此外，在以金黄色葡萄球菌美国典型菌种保藏中心（American Type Culture Collection, ATCC）25923构建的小鼠皮肤感染模型中，化合物26可有效促进伤口愈合。上述研究结果证实，化合物26及其同类衍生物在治疗金黄色葡萄球菌感染领域具备极具前景的治疗潜力。