Targeting bacterial metal dependence: material design with computational frontiers

Abstract

Antimicrobial resistance (AMR) constitutes a profound global health crisis, necessitating the development of unconventional therapeutic targets. Bacterial reliance on transition metals for metabolism, virulence, and survival creates a conserved, underexploited vulnerability that can be targeted by biomaterials to combat AMR. This review adopts a materials-oriented perspective to unify emerging metal-interfering antimicrobial strategies into three mechanistically distinct paradigms: (i) direct metal toxicity platforms, (ii) nutritional deprivation systems, and (iii) Trojan horse delivery vehicles. For each class, we extract quantitative, biology-derived design rules, such as spatio-temporal release kinetics, thermodynamic metal affinity, microenvironmental responsiveness, and surface topography matching. Finally, we highlight paradigm-shifting insights into the future of antimicrobial material innovation, including how artificial intelligence (AI) tools are now enabling de novo targeting of "undruggable" metal transporters, decoupling potency from toxicity, and creating programmable, localized antimicrobial depots. This review bridges metallobiology and biomaterials engineering to provide actionable design guidelines and a forwardlooking roadmap for next-generation, resistance-resilient antimicrobial materials.