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.