Fatty Acid-Conjugated Antimicrobial Peptides: Advances in Design, Activity, and Therapeutic Potential

Antimicrobial resistance poses a growing global health threat, necessitating the development of new therapeutic strategies. Antimicrobial peptides (AMPs) are promising candidates due to their broad-spectrum activity and multitarget mechanisms; however, their clinical translation is limited by a short in vivo half-life, susceptibility to proteolysis, cytotoxicity, and suboptimal pharmacokinetics. Fatty acid conjugation (lipidation) has emerged as an effective modification strategy to overcome these challenges by enhancing membrane interactions, antimicrobial potency, proteolytic stability, and in vivo persistence, often through binding to serum albumin. In this Perspective, we examine common lipidation approaches, including N-terminal acylation and side-chain modification, and their effects on AMP selectivity, spectrum of activity, and stability. We also highlight emerging applications of fatty-acid-conjugated AMPs in drug delivery, antibiofilm therapies, and the treatment of resistant pathogens. Finally, we discuss key safety considerations and outline future directions, including lipid optimization and AI-guided design of next-generation antimicrobial agents.