Unraveling mechanistic differences and similarities in resistance profiles to antimicrobial peptides and conventional antibiotics

Antimicrobial resistance represents a major global health challenge, particularly in the context of multidrug-resistant bacteria. Although conventional antibiotics and antimicrobial peptides (AMPs) both exert selective pressure on bacterial populations, they differ substantially in their modes of action and in the adaptive responses they elicit. This mini review compares bacterial evasion mechanisms against antibiotics and AMPs, highlighting how differences and similarities in molecular targets, cellular responses, and evolutionary trajectories influence resistance emergence and persistence. Resistance to antibiotics is often driven by specific genetic alterations, including target modification, enzymatic degradation, and active efflux, frequently resulting in stable and heritable phenotypes. By contrast, reduced susceptibility to AMPs commonly involves broader physiological adaptations, such as surface charge modification, membrane remodeling, and activation of regulatory networks, which may impose higher metabolic costs and exhibit partial reversibility. By contrasting these adaptive landscapes, this mini review underscores how mechanistic differences and similarities between antibiotic and AMP resistance can inform the interpretation of susceptibility profiles beyond binary classifications. This conceptual perspective contributes to ongoing discussions on strategies aimed at controlling the emergence and persistence of multidrug-resistant bacteria.