From metalloproteomics to drug development: bismuth-based agents as inhibitors against metallo-β-lactamase

Abstract

Metal compounds have long been used in medicine and healthcare. Metal- and metallodrug-protein interactions play a crucial role for transition metals and the action of metallodrugs. It is important to identify metal-protein interactions at a proteome-wide scale, which is difficult due to the diversity of metal-protein interactions.1,2 We developed an integrated approach to identify metal-associated proteins using bismuth, silver and gallium as an example3 as well as to quantify the metals for rapid metallome/proteome-wide profiling of metal-binding proteins. Based on our integrative metallomic approach, we have found that Bi(III) interferes with Zn(II) biochemistry in pathogens and propose to use Bi(III) compounds to inhibit metallo-β-lactamases (MBLs). 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 an anti-ulcer agent, colloidal bismuth subcitrate (CBS), and related Bi(III) compounds irreversibly inhibit different types of MBLs. CBS restores meropenem (MER) efficacy against MBL-positive bacteria in vitro, and in animal infection models.5 Surprisingly, one Bi(III) replaces two Zn(II)ions in the active site, and Bi(III) drugs can slow down the development of resistance. We demonstrate the high potential of Bi(III) compounds as the first broad-spectrum MBL inhibitors to treat MBL producing bacterial infection in combined use with existing carbapenems. Our approach has been successfully extended to Ga(III) and Ag(I), opening a new horizon for metals in biology and toxicology.