Structure-Activity Relationship Study of Antimicrobial Peptoids Against Cryptococcus neoformans

Abstract

Cryptococcal meningitis, caused by the fungal pathogen Cryptococcus neoformans, is a devastating disease with a mortality rate of over 80 percent. While usually innocuous, other fungi such as Candida albicans can cause persistent infections such as urinary tract infections, oral thrush, sepsis and more. Because of the increasing prevalence of resistance to antifungals and the high mammalian toxicity of current treatments, the development of new antifungal therapies is vital. This research project utilized a structure-activity relationship (SAR) study of a previously discovered lead antifungal peptoid termed RMG8-8. This 3-round study focused on three main structural derivatives: the lipophilic tail, aliphatic side chains, and aromatic side chains. Round 1 compounds were tested against C. albicans and C. neoformans, while the other two rounds were tested against only C. neoformans, as early derivative testing showed poor activity against the former. Cytotoxicity testing was also performed on all derivatives against mammalian HepG2 cells, and select compounds were tested for hemolytic activity against human red blood cells. While no derivative was improved across all data points, there were improvements made to hemolytic activity with derivative EJY9. There are many candidates for further investigation generated from this research, including halogenated derivatives (EJY17), compounds with increased potency against C. albicans (EJY5 and EJY7), and compounds with chiral side chains (EJY16).