2-oxoglutarate:acceptor oxidoreductase-catalyzed redox cycling effectively targets coccoid forms of Helicobacter pylori

Xudong Hang, Weiqi Lan, Huang Yanqiang, Hongming Huang, Mingjing Zhang, Liping Zeng, Ting Shi, Yuefan Bai, Zhiyu Yang, Shanwei Hu, Junfan Wang, Linlin Dong, Qian Tong, Jia Jia, Shuzhuang Bi, Qianfeng Xia, Yan Gao () and Hongkai Bi ()
Additional contact information
Xudong Hang: Hainan Medical University
Weiqi Lan: ShanghaiTech University
Huang Yanqiang: Youjiang Medical University for Nationalities
Hongming Huang: Hainan Medical University
Mingjing Zhang: ShanghaiTech University
Liping Zeng: Nanjing Medical University
Ting Shi: Nanjing Medical University
Yuefan Bai: Nanjing Medical University
Zhiyu Yang: Nanjing Medical University
Shanwei Hu: Nanjing Medical University
Junfan Wang: ShanghaiTech University
Linlin Dong: Nanjing Medical University
Qian Tong: Nanjing Medical University
Jia Jia: Nanjing Medical University
Shuzhuang Bi: Hainan Medical University
Qianfeng Xia: Hainan Medical University
Yan Gao: ShanghaiTech University
Hongkai Bi: Hainan Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Helicobacter pylori, a globally significant pathogen, plays a central etiological role in diverse gastric pathologies ranging from chronic gastritis and peptic ulcers to gastric adenocarcinoma. Although conventional antibiotics effectively inhibit or kill growing helical H. pylori, metabolically dormant coccoid forms of H. pylori exhibit considerable tolerance, posing a persistent and clinically significant challenge. Here, we report napabucasin (2-acetylfuro-1,4-naphthoquinone) as a redox-cycling antibiotic with potent bactericidal activity against both drug-resistant helical and coccoid forms of H. pylori. Notably, napabucasin does not induce acquired resistance in vitro and demonstrates superior efficacy compared to standard triple therapy in murine infection models. Mechanistic studies reveal that napabucasin acts through 2-oxoglutarate:acceptor oxidoreductase (OOR)-catalyzed futile redox cycling, generating bactericidal levels of reactive oxygen species (ROS). Compared to menaquinone 6, a proposed physiological electron acceptor, napabucasin exhibits enhanced oxidative capacity. Structural, biochemical, and microbiological analyses identify Leu44 and Lys46 within the OorD subunit as critical residues for napabucasin recognition and catalysis. These findings establish OOR-mediated redox cycling as a robust antimicrobial strategy that sustains endogenous ROS production to combat refractory H. pylori infections.

Date: 2025
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DOI: 10.1038/s41467-025-62477-4

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