Systems Approaches for Unveiling the Mechanism of Action of Bismuth Drugs: New Medicinal Applications beyond...

Metallodrugs have been widely used as diagnostic and therapeutic agents. Understanding their mechanisms of action may lead to advances in rational drug design. However, to achieve this, diversified approaches are required because of the complexity of metal-biomolecule interactions. Bismuth drugs in combination with antibiotics as a quadruple therapy show excellent success rates in the eradication of Helicobacter pylori, even for antibiotic-resistant strains, and in fact, they have been used in the clinic for decades for the treatment of infection. Understanding the mechanism of action of bismuth drugs may extend their medicinal application beyond the treatment of H. pylori infection. This Account describes several general strategies for mechanistic studies of metallodrugs, including system pharmacology and metalloproteomics approaches. The application of these approaches is exemplified using bismuth drugs. Through a system pharmacology approach, we showed that glutathione- and multidrug-resistance-associated protein 1-mediated self-propelled disposal of bismuth in human cells might explain the selective toxicity of bismuth drugs to H. pylori but not the human host. The development of metalloproteomics has enabled extensive studies of the putative protein targets of metallodrugs with a dynamic range of affinity. Continuous-flow GE-ICP-MS allows simultaneous monitoring of metals and their associated proteins with relatively high affinity on a proteome-wide scale. The fluorescence approach relies on unique M ⁿ⁺-NTA-based fluorescence probes and is particularly applicable for mining those proteins that bind to metals/metallodrugs weakly or transiently. Integration of these methods with quantitative proteomics makes it possible to maximum coverage of bismuth-associated proteins, and the sustained efficacy of bismuth drugs lies in their ability to disrupt multiple biological pathways through binding and functional perturbation of key enzymes. The knowledge acquired by mechanistic studies of bismuth drugs led to the discovery of UreG as a new target for the development of urease inhibitors. The ability of Bi(III) to inhibit metallo-β-lactamase (MBL) activity through displacement of the Zn(II) cofactor renders bismuth drugs new potential as broad-spectrum inhibitors of MBLs. Therefore, bismuth drugs could be repurposed together with clinically used antibiotics as a cotherapy to cope with the current antimicrobial resistance crisis. We anticipate that the methodologies described in this Account 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 will inspire researchers in relevant fields to engage in the rational design of drugs and reuse of existing drugs, eventually leading to the development of new effective therapeutics.