24th international Biometals webinars

The global challenge of antimicrobial resistance necessitates novel therapeutic strategies. This study explores the potential of metal-based drugs, particularly bismuth and gold compounds, to disrupt metallostasis in bacterial and viral pathogens. Bismuth compounds were found to restore antibiotic activity against multidrug-resistant bacteria, including those producing metallo-β-lactamases (NDM-1, VIM-2, IMP-4). Mechanistically, bismuth(III) displaces zinc from the active site of NDM-1, with one equivalent of bismuth replacing two equivalents of zinc, leading to irreversible enzyme inhibition exceeding 90%. Similarly, gold(I) compounds, such as Auranofin, targeted the zinc-binding domain of MCR-1, an enzyme conferring colistin resistance, thereby restoring antibiotic efficacy. *In vivo* models demonstrated that combination therapy with bismuth or gallium drugs significantly reduced bacterial load by 2-3 log units and increased survival rates to 75-100% in resistant bacterial infections. Furthermore, bismuth was shown to disrupt iron homeostasis in bacteria, interfering with iron-related proteins and iron-sulfur clusters. Beyond bacteria, bismuth compounds inhibited viral helicase activity by targeting zinc-finger domains, suppressing viral load in infected animal models and reducing the duration of viral infection in small-scale clinical trials by 1-3 days compared to conventional antivirals, especially when co-administered with N-acetyl-L-cysteine to enhance absorption. These findings highlight the disruption of metal homeostasis as a promising strategy for combating both antimicrobial resistance and viral infections. Introduction to the 24th international Biometals webinars Disruption of metal homeostasis for drug development against bacterial infection The next pandemic is probably the crisis of antibiotic resistance (1,2). New arsenals are urgently required for infections caused by resistant bacteria. Targeting metal homeostasis, particularly iron homeostasis could be an effective approach against infections by resistant bacteria (3,4). Cefidercofol (FDC, Fetroja®) is designed to ‘smuggle an antibiotics’ into bacterial cells through the bacteria’s uptake of ferric iron, enhancing its bactericidal effect. We developed a dual ‘Trojan Horse’ strategy, where a metal-based drug and sideromycins (e.g. Cefidercofol), a class of antibiotic structurally resembling ferric iron, work together in combating antibiotic-resistant bacteria efficiently (5). We found that bismuth drugs mimicking ferric iron enter bacteria cells and inhibit key bacterial enzymes, achieving a dual function. We subsequently found that bismuth complexes resensitize drug resistant Pseudomonas aeruginosa to multiple antibiotics. Our metalloproteomic study demonstrated that bismuth drugs/complexes disrupt iron homeostasis by specifically binding to siderophore and Fe-proteins/enzymes (6). Inside the bacteria, Bi(III) complexes specifically targets Fe-S cluster enzymes, leading to the inhibition of respiratory complexes. We further demonstrated in vivo efficacy of combination of a bismuth drug with certain antibiotics. These findings lay a solid foundation for future efforts to combat resistant bacterial infections by a biometal and metallomic approach.