From Host-Derived Pressures to the Environmental Anti-Antimicrobial Peptides Resistome: Mechanisms, Reservoirs and Implications for Therapeutic Peptide Design

Antimicrobial peptides (AMPs) are increasingly promoted as alternatives or complements to conventional antibiotics, yet growing evidence demonstrates that resistance to AMPs is neither rare nor incidental. Here, we define the anti-AMP resistome as a coordinated network of genetic, regulatory, and physiological mechanisms that enable bacteria to tolerate or evade AMP-mediated stress. We synthesize advances in understanding how envelope remodeling, efflux and sequestration, extracellular proteolysis, biofilm-associated buffering, and inducible stress responses collectively shape AMP susceptibility. We further distinguish transient, inducible tolerance from stable, heritable resistance, and discuss how chronic subinhibitory exposure can drive their evolutionary interconversion. Extending beyond clinical pathogens, we highlight environmental microbiomes as major reservoirs of anti-AMP determinants with implications for horizontal transfer and One Health risk. Finally, we argue that AMP development and deployment must adopt a resistome-aware framework that integrates molecular mechanisms, evolutionary dynamics, and environmental context to preserve long-term therapeutic efficacy.