Abstract
Antimicrobial resistance (AMR) is a mounting global health crisis demanding novel, sustainable therapeutic strategies beyond traditional antibiotics. Ultra-short cationic β-peptides have emerged as a promising class of synthetic antimicrobial foldamers with broad-spectrum activity, remarkable proteolytic stability, and low resistance potential. Designed through rational approaches, these 2-10 residue peptides leverage amphipathicity, structural rigidity, and electrostatic interactions to disrupt microbial membranes, biofilms, and even intracellular pathogens. Notably, they exhibit synergistic effects with conventional antibiotics and minimal toxicity to mammalian cells. Emerging in vivo studies in murine models further suggest that ultra-short β-peptides can reduce pathogen burden and improve survival, although the available data remain limited and warrant careful interpretation. This review provides a comprehensive overview of their design, mechanism of action, antimicrobial spectrum, including bacteria, fungi, viruses, and protozoa, and relevance to One Health frameworks. Key translational bottlenecks, including delivery challenges, immunogenicity, pharmacokinetics, and regulatory hurdles, are critically assessed. We also identify major research gaps and propose future directions to fully harness the therapeutic potential of ultra-short β-peptides against multidrug-resistant infections.