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<p><i>Helicobacter pylori</i>, 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 <i>H. pylori</i>, metabolically dormant coccoid forms of <i>H. pylori</i> 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 <i>H. pylori</i>. 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 <i>H. pylori</i> infections.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月29日

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  • 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,
  • Hongkai Bi

摘要

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.