Open AccessDiscovery and Characterization of a Rapidly Fungicidal and Minimally Toxic Peptoid against Cryptococcus neoformans
Author(s) -
R. Madison Green,
Kevin L. Bicker
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00327
Subject(s) - peptoid , cryptococcus neoformans , candida albicans , antimicrobial , microbiology and biotechnology , lysis , oncolytic virus , corpus albicans , chemistry , cytotoxicity , biology , biochemistry , peptide , cancer research , in vitro , tumor cells
A limited number of antifungals are available to treat infections caused by fungal pathogens such as Cryptococcus neoformans and Candida albicans . Current clinical antifungals are generally toxic, and increasing resistance to these therapies is being observed, necessitating new, effective, and safe antifungals. Peptoids, or N-substituted glycines, have shown promise as antimicrobial agents against bacteria, fungi, and parasites. Herein we report the discovery and characterization of an antifungal peptoid termed RMG8-8. This compound was originally discovered from a combinatorial peptoid library using the Peptoid Library Agar Diffusion assay to screen against C. albicans . Though the efficacy of RMG8-8 against C. albicans was modest (25 μg/mL), the efficacy against C. neoformans was excellent (1.56 μg/mL). Cytotoxicity against a panel of cell lines proved RMG8-8 to be minimally toxic, with selectivity ratios ranging from 34 to 121. Additional studies were carried out to determine the pharmacological importance of each peptoid monomer in RMG8-8, characterize the killing kinetics of this compound against C. neoformans ( t 1/2 = 6.5 min), and evaluate plasma protein binding and proteolytic stability. Finally, a liposomal lysis assay suggested that RMG8-8 likely exerts fungal killing through membrane permeabilization, the generally accepted mechanism of action for most antimicrobial peptides and peptoids.