title: Functional disruption of peroxiredoxin by bismuth antiulcer drugs attenuates Helicobacter pylori survival.
abstract: 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 (Kd) of Bi(III) to AhpC of 3.0 (±1.0) × 10-24M. 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.
authors.affiliation: Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, People's Republic of China.
authors.forename: Yuen-Yan
authors.initials: YY
authors.lastname: Chang
authors.affiliation: Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, People's Republic of China.|Faculty of Dentistry, The University of Hong Kong, Sai Ying Pun, Hong Kong, People's Republic of China.
authors.forename: Tianfan
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, People's Republic of China.
authors.forename: Xinming
authors.initials: X
authors.lastname: Yang
authors.affiliation: Faculty of Dentistry, The University of Hong Kong, Sai Ying Pun, Hong Kong, People's Republic of China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, People's Republic of China. hsun@hku.hk.
authors.forename: Hongzhe
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, People's Republic of China. hylichem@hku.hk.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001729:Bismuth / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016480:Helicobacter pylori / Q000737:chemistry / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D010544:Peroxidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000897:Anti-Ulcer Agents; D001426:Bacterial Proteins; D010544:Peroxidases; C508531:ahpC protein, Helicobacter pylori; D001729:Bismuth
keywords: Bismuth drug; Enzyme; Molecular mechanism; Oxidative stress; Peroxiredoxin