Antifungal Imidazole‐Decorated Cationic Amphiphiles with Markedly Low Hemolytic Activity

Abstract

Herein we report that an imidazole-decorated cationic amphiphile derived from the pseudo-disaccharide nebramine has potent antifungal activity against strains of Candida glabrata pathogens. In combination with the natural bis-benzylisoquinoline alkaloid tetrandrine the reported antifungal cationic amphiphile demonstrated synergistic antifungal activity against Candida albicans pathogens. This unique membrane disruptor caused no detectible mammalian red blood cell hemolysis at concentrations up to more than two orders of magnitude greater than its minimal inhibitory concentrations against the tested C. glabrata strains. We provide evidence that potency against C. glabrata may be associated with differences between the drug efflux pumps of C. albicans and C. glabrata. Imidazole decorated-cationic amphiphiles show promise for the development of less toxic membrane-disrupting antifungal drugs and drug combinations.

Localizing Antifungal Drugs to the Correct Organelle Can Markedly Enhance their Efficacy

“…All MICs were determined using the broth double‐dilution method starting with 64 μg/mL of each compound . Cells were grown in RPMI 1640 medium at 37 °C under 5 % CO 2 for 24 h. Each concentration was tested in triplicate, and results were confirmed by two independent sets of experiments.…”

Cationic Amphiphiles Induce Macromolecule Denaturation and Organelle Decomposition in Pathogenic Yeast

“…The incidence of fungal infections has risen sharply in recent decades and the prevention and treatment of these infections relies on a very limited number of classes of antifungal drugs . Therefore, in recent years, several research groups, including ours, have been engaged in the study and development of membrane‐disrupting antifungal cationic amphiphiles based on the pseudo‐oligosaccharide structures of aminoglycoside (AG) antibiotics . The design of these antifungal agents is based on the attachment of hydrophobic residues to one or more positions of the AG scaffold.…”

Localizing Antifungal Drugs to the Correct Organelle Can Markedly Enhance their Efficacy

“…[28] Cells were grown in RPMI 1640 medium at 37 8 8Cunder 5% CO 2 for 24 h. Each concentration was tested in triplicate, and results were confirmed by two independentsets of experiments. [28] Cells were grown in RPMI 1640 medium at 37 8 8Cunder 5% CO 2 for 24 h. Each concentration was tested in triplicate, and results were confirmed by two independentsets of experiments.…”

“…Thea ntifungal activity of the 1,2,4-triazole-based azoles 2 and 3 was compared to that of the corresponding 1,2,3-triazole-based azoles 4 and 5 and to FLC by the broth double dilution method [28] using ap anel composed of five different Candida species (Strains A-K, Table 1). Notably,the antifungal activity of azole 3 was improved significantly relative to both FLC and to the azole 2 in all of the species.…”