LAUSR

Antimicrobial peptides are proving to be promising lead compounds for therapeutics. The major disadvantage of antimicrobial peptides is their proteolytic instability in the body with half-lives averaging less than an hour. Peptoids, or N-substituted glycines, have emerged as a promising field of peptidomimetics by retaining the beneficial properties of antimicrobial peptides while improving on their stability. Herein we evaluate peptoid derivatives of ultra-short lipophilic antimicrobial peptides, comparing their potency side-by-side against the most prevalent multidrug resistant bacteria (ESKAPE) and yeast pathogens (Candida albicans and Cryptococcus neoformans). Both peptide and peptoid counterparts were most effective against Gram-positive bacteria with minimum inhibitory concentration (MIC) values as low as 1.6 and 6.3 µg/mL, respectively. In general, peptides retained better antimicrobial activity than their peptoid counterparts, however, certain peptoids proved to be more effective than peptides against Gram-negative bacteria. For example, peptoid MG10 displayed an MIC of 6.3 µg/mL against Pseudomonas aeruginosa compared to the peptide counterpart with an MIC of 100 µg/mL. All compounds tested were more potent against C. neoformans compared to C. albicans. Cytotoxicity analysis indicated that in general, peptoids were slightly less toxic than their peptide counterparts. Additionally, trypsin rapidly degraded one of the peptides evaluated while having no effect on comparable peptoids, demonstrating the proteolytic stability of peptoids.