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

Journal: Journal of medicinal chemistry
Published Date: May 29, 2025

Abstract

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 and demonstrated exceptional activity, reducing bacterial loads of methicillin-resistant (MRSA) and 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.

Authors

  • Fangjie Wang
    The First Research Department, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical Center of PLA, Army Medical University, Chongqing 400042, China.
  • Sheng-Li Niu
    Department of Medicinal Chemistry, Army Medical University, Chongqing 400038, China.
  • Wei Li
    Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
  • Hong-Yuan Liu
    Department of Medicinal Chemistry, Army Medical University, Chongqing 400038, China.
  • Xue Gong
    Department of Biology and Medicine, China University of Mining and Technology of School of Chemical Engineering & Technology, Xuzhou, Jiangsu, China (mainland).
  • Xiaoyuan Ma
    State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China; Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi 214122, PR China.
  • Bo Zhao
    State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
  • Dongmei He
    Department of Neurology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, 637000, Sichuan, China.
  • Jinyu Xia
    Department of Medicinal Chemistry, Army Medical University, Chongqing 400038, China.
  • Liang Gong
    Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
  • Yiqin Cui
    The First Research Department, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical Center of PLA, Army Medical University, Chongqing 400042, China.
  • Rui Gao
    School of Control Science and Engineering, Shandong University, Jinan, China.
  • Huaping Liang
    The First Research Department, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical Center of PLA, Army Medical University, Chongqing 400042, China.
  • Jing Gu
    Department of Epidemiology and Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, China.
  • Qin Ouyang
    United States Department of Agriculture, Agricultural Research Service, U.S. National Poultry Research Center, Athens, GA, 30605, USA.

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