Mechanism of Action of Antifungal Peptoids

Abstract

Due to the rise of drug resistant strains of fungal pathogens such as Cryptococcus neoformans and Candida albicans, there has been a need to identify new antifungal agents. In comparison to naturally produced antifungal peptides, antifungal peptoids, sequencespecific oligo-N-substituted glycines, mainly differ in structure, which prevents protease recognition giving higher bioavailability. Previous studies have shown that peptoids are effective fungicides. RMG8-8 and RMG9-11, two peptoids recently discovered in the Bicker Lab, have proven to be effective antifungal agents against C. neoformans and C. albicans, respectively. Reported here will be studies to determine the mechanism of action and other vital therapeutic properties of RMG8-8 and RMG9-11 using various biochemical and microbiological assays. Preliminary results of critical micelle concentration, the minimum concentration of a compound needed to form micelles, testing indicate that RMG8-8 as well as RMG9-11 do not exist as micelles at their minimum inhibitory concentrations, but rather function unimolecularly. Using a PAMPA assay, it was found that RMG8-8 is likely unable to penetrate the blood brain barrier (BBB). However, RMG9- 11 demonstrated good permeability, indicating that it may be able to penetrate the BBB to treat dangerous neurological infections of fungi. Through a cytoplasmic membrane depolarization assay of RMG9-11 against C. albicans, it was discovered that the peptoid was able to depolarize the cell membrane in a concentration dependent manner. In future work, assays will be conducted to further understand the mechanism of action of both peptoid compounds to address the rising concern of drug resistant strains of fungal pathogens.