Discovery and Characterization of a Rapidly Fungicidal and Minimally Toxic Peptoid against Cryptococcus neoformans.

Abstract

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.