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.