Discovery of CYP1A1 Inhibitors for Host-Directed Therapy against Sepsis.

Bacterial sepsis remains a leading cause of death globally, exacerbated by the rise of multidrug resistance (MDR). Host-directed therapy (HDT) has emerged as a promising nonantibiotic approach to combat infections; thus, multiple HDT targets have been identified. However, the translation of HDT targets into therapeutic drugs, particularly small-molecule drugs, remains rare. Our study focuses on cytochrome P4501A1 (CYP1A1), a negative regulator of host antiinfection capabilities. Using deep learning, virtual screening, and biological evaluation, we identified novel small-molecule inhibitors of CYP1A1. After structural optimization, compounds 38 and 47 demonstrated exceptional activity, reducing bacterial loads of methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii by over 70% by enhancing macrophage phagocytosis. This work highlights CYP1A1 as a valuable HDT target and shows that inhibiting it with a single small-molecule compound can offer a potential solution to treat MDR bacterial-induced sepsis.