Functional disruption of peroxiredoxin by bismuth antiulcer drugs attenuates Helicobacter pylori survival
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Bismuth drugs have been used clinically to treat infections from Helicobacter pylori, a pathogen that is strongly related to gastrointestinal diseases even stomach cancer. Despite extensive studies, the mechanisms of action of bismuth drugs are not fully understood. Alkyl hydroperoxide reductase subunit C (AhpC) is the most abundant 2-cysteine peroxiredoxin, crucial for H. pylori survival in the host by defense of oxidative stress. Herein we show that a Bi(III) antiulcer drug (CBS) binds to the highly conserved cysteine residues (Cys49 and Cys169) with a dissociation constant (K d) of Bi(III) to AhpC of 3.0 (±1.0) × 10−24 M. Significantly the interaction of CBS with AhpC disrupts the peroxiredoxin and chaperone activities of the enzyme both in vitro and in bacterial cells, leading to attenuated bacterial survival. Moreover, using a home-made fluorescent probe, we demonstrate that Bi(III) also perturbs AhpC relocation between the cytoplasm and membrane region in decomposing the exogenous ROS. Our study suggests that disruption of redox homeostasis by bismuth drugs via interaction with key enzymes such as AhpC contributes to their antimicrobial activity.
KeywordsBismuth drug Enzyme Oxidative stress Peroxiredoxin Molecular mechanism
This work was supported by the Research Grants of Council of Hong Kong (703913, 17304614, 17305415, 17333616), Livzon Pharmaceutical Group, the University of Hong Kong (for an emerging Strategic Research Theme on Integrative Biology). We thank the assistance of Li Ka Shing Faculty of Medicine Faculty Core Facility, The University of Hong Kong. We thank Prof. Patrick Chiu Yat Woo (Department of Microbiology, LKS Faculty of Medicine) for his generous offer of clinical isolate of H. pylori strain. We thank Dr. Ligang Hu for his helpful comments and suggestions and Dr. Yau-Tsz Lai for suggestions on microscopic analysis.
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