Self-Destructible Antibiotics: Programmable Drug Degradation as a Design Strategy to Mitigate Antimicrobial Resistance

Abstract

Antimicrobial resistance (AMR) continues to expand despite sustained efforts in antibiotic discovery, stewardship, and infection control. A key yet under addressed contributor to resistance evolution is the prolonged biological activity of antibiotics beyond their therapeutic window, particularly following excretion into environmental systems. Persistent low-level exposure imposes continuous selective pressure on microbial communities, accelerating resistance emergence and dissemination across clinical and ecological boundaries. Self-destructible antibiotics (SDAs) have emerged as a novel design paradigm that seeks to align antimicrobial efficacy with controlled post-therapeutic deactivation. Rather than maximizing chemical stability alone, SDAs incorporate built-in mechanisms that enable predictable inactivation after clinical utility is achieved. This review synthesizes advances in chemical self-immolative systems, nano pharmaceutical delivery platforms, enzyme- and microbiome-responsive degradation strategies, and synthetic biology–based control mechanisms that collectively enable programmable antibiotic lifespans. By integrating concepts from green chemistry, evolutionary biology, and precision medicine, SDAs represent a shift from use-dependent stewardship to design-enforced responsibility. We critically evaluate the conceptual foundations, technological approaches, translational barriers, and sustainability implications of SDAs, positioning them as a forward-looking strategy to reduce resistance selection while preserving therapeutic effectiveness.