Metal-Based Approaches for the Fight against Antimicrobial Resistance: Mechanisms, Opportunities, and Challenges.

The rapid emergency and spread of antimicrobial-resistant (AMR) bacteria and the lack of new antibiotics being developed pose serious threats to the global healthcare system. Therefore, the development of more effective therapies to overcome AMR is highly desirable. Metal ions have a long history of serving as antimicrobial agents, and metal-based compounds are now attracting more interest from scientific communities in the fight against AMR owing to their unique mechanism. Moreover, they may also serve as antibiotic adjuvants to enhance the efficacy of clinically used antibiotics. In this perspective, we highlight important showcase studies in the last 10 years on the development of metal-based strategies to overcome the AMR crisis. Specifically, we categorize these metallo-antimicrobials into five classes based on their modes of action (i.e., metallo-enzymes and metal-binding enzyme inhibitors, membrane perturbants, uptake/efflux system inhibitors/regulators, persisters inhibitors, and oxidative stress inducers). The significant advantages of metallo-antimicrobials over traditional antibiotics lie in their multitargeted mechanisms, which render less likelihood to generate resistance. However, we notice that such modes of action of metallo-antimicrobials may also raise concern over their potential side effects owing to the low selectivity toward pathogens and host, which appears to be the biggest obstacle for downstream translational research. We anticipate that combination therapy through repurposing (metallo)drugs with antibiotics and the optimization of their absorption route through formulation to achieve a target-oriented delivery will be a powerful way to combat AMR. Despite significant challenges, metallo-antimicrobials hold great opportunities for the therapeutic intervention of infection by resistant bacteria.