Antimicrobial α-Peptoids/Polypeptoids: Molecular Design and Therapeutic Assemblies

The global health crisis of antibiotic-resistant bacteria necessitates the development of novel antimicrobial agents. Natural antimicrobial peptides (AMPs) represent a promising therapeutic strategy, but their susceptibility to proteolytic degradation in vivo severely limits their clinical application. Peptoids, or N-substituted glycine oligomers, have emerged as a robust biomimetic alternative. By shifting the side chain from the α-carbon to the backbone nitrogen atom, peptoids lack amide hydrogen donors, rendering them resistant to protease hydrolysis while maintaining a peptide-mimetic architecture. In this review, we first compare synthetic strategies (solid-phase synthesis versus solution polymerization) and outline key molecular design principles that govern antimicrobial activity and biocompatibility. We further assess self-assembled supramolecular structures that confer emergent properties, ranging from enhanced membrane penetration to stimuli-responsive release. Finally, we discuss prevailing challenges and propose future directions for translating these promising materials into effective antimicrobial therapies. Beyond combining recent advances, this review establishes a molecular-to-assembly framework to guide the design of next-generation antimicrobial agents.