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

Antimicrobial resistance has emerged as a critical threat to global health, with drug-resistant infections. Antimicrobial peptides (AMPs) are a promising class of therapeutics to address this crisis due to their broad-spectrum activity, ability to target multiple sites, and reduced susceptibility to resistance development. However, native AMPs often face limitations, including short in vivo half-life, susceptibility to proteolysis, and suboptimal pharmacokinetics. Fatty acid conjugation (lipidation) of AMPs has emerged as an effective strategy to enhance their therapeutic potential. Covalently attaching hydrophobic fatty acid chains to peptide sequences is used to improve membrane binding and antimicrobial potency, increase proteolytic stability and half-life (often via serum albumin binding), and modulate selectivity toward microbial over host cells. This review provides an overview of fatty acid-conjugated AMPs (FAMPs). We first summarize the fundamental mechanisms of AMP action and then discuss the rationale for fatty acid modification. We describe common conjugation strategies (e.g., N-terminal acylation, side-chain attachment chemistry) and examine how lipidation affects antimicrobial activity, spectrum, stability against degradation, and selectivity. We highlight applications of lipopeptide AMPs in drug delivery (including improved oral uptake and tissue targeting), anti-biofilm interventions, and combating multi-drug-resistant strains. Safety and toxicity considerations are addressed, emphasizing the balance between increased hydrophobicity and host cell compatibility. Finally, we discuss future directions and perspectives in this field, such as optimizing fatty acid structure to maximize efficacy and safety, using artificial intelligence in design, and integrating FAMPs into next-generation therapeutic strategies.