Unveiling the Mechanism of Action of Bismuth Drugs by an Integrative Metallomic Approach: New Medicinal Applications Beyond Helicobacter Pylori Infection

Abstract

Metallodrugs have been widely used as either diagnostic or therapeutic agents. It is crucial to understand their mechanisms of action to advance drug design. To achieve this, an integrative approach is required due to the complexity of metal-biomolecule interactions. Bismuth drugs in combination with antibiotics have been used in clinic for decades for the treatment of Helicobacter pylori (H. pylori) infection including antibiotic resistance strains. We developed a system pharmacology and metalloproteomics approaches consisting of continuous-flow gel electrophoresis and inductively coupled plasma mass spectrometry, LA-ICP-MS, IMAC and fluorescence to identify metal-associated proteins in cells using bismuth drugs as an example (1-3). The knowledge acquired by these studies enables UreG to be discovered as a new target for the development of urease (4). We have also found that Bi(III) selectively interfere with Zn(II) biochemistry in pathogens (5). Infections caused by metallo-β-lactamases (MBLs), e.g., New Delhi metallo-β- lactamase 1(NDM-1) producing bacteria are extremely difficult to treat (4). We show that colloidal bismuth subcitrate (CBS), and related Bi(III) compounds irreversibly inhibit different types of MBLs via the metal displacement mechanism with one Bi(III) displacing two Zn(II) ions. CBS restores meropenem (MER) efficacy against MBL-positive bacteria in vitro, and in animal infection models (6). Therefore, bismuth drugs could be repurposed together with clinically used antibiotics as co-therapy to cope with current antimicrobial resistance crisis. We anticipate that the methodologies described are generally applicable for understanding the (patho)physiological roles of metals/metallodrugs. Our mechanism-guided discovery of new druggable targets as well as new medicinal applications of bismuth drugs may eventually lead to the development of new effective therapeutics. Financial support by the the Research Grants Council of Hong Kong (17307017 and R7070-18), the University of Hong Kong, and Norman and Cecelia Yip Foundation for financial support is gratefully acknowledged.