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 (K ) of Bi(III) to AhpC of 3.0 (±1.0) × 10 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.

Multi-omics and temporal dynamics profiling reveal disruption of central metabolism inHelicobacter pylorion bismuth treatment

“… 71 We have demonstrated in previous studies that bismuth impairs the oxidative defense systems in H. pylori by binding and functionally disrupting key enzymes such as catalase, arginase and peroxiredoxin. 10 , 72 Herein, we observed at the transcriptome level the down-regulation of genes tpx , trxA and trxB encoding key antioxidant enzymes, 73 and genes mutS and recA encoding DNA repair enzymes, 74 , 75 further corroborated the reduced oxidative defense ability of H. pylori upon CBS treatment. Moreover, we detected elevated levels of intracellular ROS induced by CBS ( Fig.…”

The synergy of resveratrol and alcohol against Helicobacter pylori and underlying anti‐ Helicobacter pylori mechanism of resveratrol

“…It has been reported that sodB mutants were more sensitive to oxidative stress and defective to colonize the mouse stomach (Seyler et al ). Two peroxiredoxins (HP1563, HP0390) were upregulated in this study, which were crucial for H. pylori survival in the host by defence of oxidative stress (Chang et al ). A recent study suggested that urease can protect H. pylori against oxidative damage via Met residue‐mediated quenching of harmful oxidants (Schmalstig et al ).…”

Cytotoxicity of biologically synthesised bismuth nanoparticles against HT‐29 cell line

“…It has indicated that Bi enhanced the level of alkyl hydroperoxide reductase subunit C (AhpC) which is the most abundant 2‐cysteine peroxiredoxin in decomposing the exogenous reactive oxygen species (ROS) contributes to anti‐bacterium mechanisms [30]. Therefore, induction the ROS or OS damages are important mechanisms against bacterium especially H. Pylori might be accelerated by Bi compounds.…”