From metalloproteomics to drug development: metallo-based antibiotic adjuvants for superbug infections

Abstract

At least 25 elements are essential for lives and metal compounds have long been used in medicine and healthcare. Metal- and metallodrug-protein interactions play a crucial role for metallodrugs. It is critical to identify metal-protein interactions at a proteome-wide scale which are difficult due to diversity of metal-protein interactions 1,2. We developed a system approach consisting of continuous-flow gel electrophoresis and inductively coupled plasma mass spectrometry, LA-ICP-MS, IMAC and fluorescence to identify metal-associated proteins using bismuth antiulcer drug as an example 3. We also integrate metalloproteomics with metabolomics, transcriptomics and bioinformatics to examine multiple cellular changes to the numerous intracellular process affected 4. Based on our integrative metallomic approach, we have found that Bi(III) interfere with Zn(II) biochemistry in pathogens. We propose to use Bi(III) compounds to inhibit metallo-β-lactamases (MBLs) based on its selective toxicity towards pathogens whereas almost without toxicity to humans. Infections caused by metallo-β-lactamases (MBLs), e.g., New Delhi metallo-β-lactamase 1(NDM-1) producing bacteria are extremely difficult to treat 5. We show that an anti-ulcer agent, 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 as revealed by X-ray crystallography. CBS restores meropenem (MER) efficacy against MBL-positive bacteria in vitro, and in animal infection models 6. Importantly, we show that CBS slows down the development of resistance in NDM-1 producing bacteria. We demonstrate a 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. The approach can readily be extended to other types of infections caused by superbugs.