The rise and future of peptide-based antimicrobials.

Abstract

The escalating threat of antimicrobial resistance has renewed global interest in peptide-based antibiotics as adaptable and effective alternatives to conventional small molecules. Peptides possess diverse mechanisms of action, high target specificity, and structural flexibility, which collectively limit the emergence of resistance. This review outlines recent advances spanning the discovery, optimization, and application of peptide antibiotics, from their biological origins and structural classifications to emerging strategies involving artificial intelligence, synthetic biology, and modern delivery technologies. Peptide antibiotics can be categorized by origin as natural, semi-synthetic, or fully synthetic, and further organized by structural class such as α-helical, β-sheet, cyclic, and extended forms. They are also grouped by function into membrane-targeted and non-membrane-targeted types. These classification schemes are not only descriptive but also critical for understanding the therapeutic potential of peptides, as each category presents distinct advantages and engineering challenges that influence stability, specificity, and overall clinical performance. Advances in artificial intelligence, synthetic biology, and continuous manufacturing are reshaping how peptide drugs are designed and produced, while innovations in drug delivery systems are addressing critical issues of stability and bioavailability. Together, these developments are laying the foundation for a new generation of peptide-based therapeutics capable of meeting the evolving challenges of antimicrobial resistance.