Unlocking the potential of antimicrobial lipopeptides: a pathway to combat multidrug-resistant pathogens

Antimicrobial lipopeptides (AMLPs) have emerged as a promising class of therapeutic agents against multidrug-resistant pathogens due to their unique amphiphilic structure and multimodal mechanisms of action. This review systematically summarizes the microbial origins and structural classification of AMLPs, elucidates their membrane-targeting and intracellular bactericidal mechanisms, and explores strategies for evading resistance. Furthermore, we analyze their structure-activity relationships (SAR) at the primary, secondary, and self-assembled structural levels, proposing optimization strategies based on experimental design and computational simulations. Finally, we discussed the clinical applications of AMLPs. By integrating mechanistic analysis with a rational design framework, this article aims to accelerate the development of next-generation AMLPs with enhanced efficacy, selectivity, and reduced resistance risk, providing strategic pathways to address the global antimicrobial resistance crisis.