Multi-omics and temporal dynamics profiling reveal disruption of central metabolism in Helicobacter pylori on bismuth treatment

Integration of multi-omics enables uncovering cellular responses to stimuli or the mechanism of action of a drug at a system level. Bismuth drugs have long been used for the treatment of Helicobacter pylori infection and their antimicrobial activity was attributed to dysfunction of multiple proteins based on previous proteome-wide studies. Herein, we investigated the response of H. pylori to a bismuth drug at transcriptome and metabolome levels. Our multi-omics data together with bioassays comprehensively reveal the impact of bismuth on a diverse array of intracellular pathways, in particular, disruption of central carbon metabolism is systematically evaluated as a primary bismuth-targeting system in H. pylori. Through temporal dynamics profiling, we demonstrate that bismuth initially perturbs the TCA cycle and then urease activity, followed by the induction of oxidative stress and inhibition of energy production, and in the meantime, induces extensive down-regulation in H. pylori metabolome. The present study thus expands our knowledge on the inhibitory actions of bismuth and provides a novel systematic perspective of H. pylori in response to a clinical drug that sheds light on enhanced therapeutic methodologies.