Integrative approach for analysis of proteome-wide response to bismuth drugs in Helicobacter pylori
Bismuth drugs, despite being used clinically for decades, surprisingly remain used and effective for the treatment of Helicobacter pylori infection even for resistant strains when co-administrated with antibiotics. The molecular mechanisms underlying the clinically sustained susceptibility of H. pylori to bismuth drugs remain elusive. Herein, we report that integration of in-house metalloproteomics and quantitative proteomics allows comprehensive uncovering of bismuth associated proteomes including 63 bismuth-binding and 119 bismuth-regulated proteins from Helicobacter pylori with over 60% being annotated with catalytic functions. Through bioinformatics analysis in combination with bioassays, we demonstrate that bismuth drugs disrupt multiple essential pathways in the pathogen including ROS defense and pH buffering by binding and functional perturbation of a number of key enzymes. Moreover, we discover that HpDnaK may serve as a new target of bismuth drugs to inhibit bacterium-host cell adhesion. The integrative approach we report here provides a novel strategy to unveil molecular mechanisms of antimicrobial metals against pathogens in general. This study sheds light on the design of new types of antimicrobial agents with multiple targets to tackle current crisis of antimicrobial resistance.