Structure-Activity Relationship Study of Antimicrobial Peptide with Cross-Kingdom Activity

The widespread emergence of antibiotic-resistant pathogens poses a significant global health challenge and underscores the need for novel approaches to accelerate antimicrobial discovery. Antimicrobial peptides (AMPs) have gained attention as promising candidates due to their broad-spectrum activity, including efficacy against multidrug-resistant bacterial strains. SAJO-2, an antimicrobial peptide developed by Sarojini and colleagues, features a tryptophan zipper-like motif incorporating a central d-Phe-2-Abz unit, where 2-Abz functions as a conformationally constrained β-turn-inducing peptidomimetic scaffold. Modification of SAJO-2 in prior joint work from our groups through differential fluorination enhanced its antimicrobial potency; however, it also increased susceptibility to enzymatic digestion by β-trypsin. To address this limitation, the current research focuses on improving the overall efficacy of SAJO-2 through the incorporation of D-amino acids, beta backbone modifications, and a bulky pentafluorinated amino acid residue. All modified peptides exhibit resistance to enzymatic degradation, while antimicrobial activity was retained to differing degrees across organisms.