An Antifungal Benzimidazole Derivative Inhibits Ergosterol Biosynthesis and Reveals Novel Sterols.

Abstract

Fungal infections are a leading cause of morbidity and death for hospitalized patients, mainly because they remain difficult to diagnose and to treat. Diseases range from widespread superficial infections such as vulvovaginal infections to life-threatening systemic candidiasis. For systemic mycoses, only a restricted arsenal of antifungal agents is available. Commonly used classes of antifungal compounds include azoles, polyenes, and echinocandins. Due to emerging resistance to standard therapies, significant side effects, and high costs for several antifungals, there is a need for new antifungals in the clinic. In order to expand the arsenal of compounds with antifungal activity, we previously screened a compound library using a cell-based screening assay. A set of novel benzimidazole derivatives, including (S)-2-(1-aminoisobutyl)-1-(3-chlorobenzyl)benzimidazole (EMC120B12), showed high antifungal activity against several species of pathogenic yeasts, including Candida glabrata and Candida krusei (species that are highly resistant to antifungals). In this study, comparative analysis of EMC120B12 versus fluconazole and nocodazole, using transcriptional profiling and sterol analysis, strongly suggested that EMC120B12 targets Erg11p in the ergosterol biosynthesis pathway and not microtubules, like other benzimidazoles. In addition to the marker sterol 14-methylergosta-8,24(28)-dien-3β,6α-diol, indicating Erg11p inhibition, related sterols that were hitherto unknown accumulated in the cells during EMC120B12 treatment. The novel sterols have a 3β,6α-diol structure. In addition to the identification of novel sterols, this is the first time that a benzimidazole structure has been shown to result in a block of the ergosterol pathway.

• Authors: Petra Keller, Christoph Müller, Isabel Engelhardt, Ekkehard Hiller, Karin Lemuth, Holger Eickhoff, Karl-Heinz Wiesmüller, Anke Burger-Kentischer, Franz Bracher, Steffen Rupp
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 10 Pg. 6296-307 (Oct 2015) ISSN: 1098-6596 [Electronic] United States
• PMID: 26248360 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antifungal Agents
• Benzimidazoles
• Fungal Proteins
• Small Molecule Libraries
• 14-methylergosta-8,24(28)-dien-3,6-diol
• Fluconazole
• Sterol 14-Demethylase
• Nocodazole
• Ergosterol

Topics

• Antifungal Agents (chemistry, pharmacology)
• Benzimidazoles (chemistry, pharmacology)
• Candida (drug effects, growth & development, metabolism)
• Candida albicans (drug effects, growth & development, metabolism)
• Candida glabrata (drug effects, growth & development, metabolism)
• Ergosterol (analogs & derivatives, antagonists & inhibitors, biosynthesis, isolation & purification)
• Fluconazole (chemistry, pharmacology)
• Fungal Proteins (antagonists & inhibitors, metabolism)
• High-Throughput Screening Assays
• Nocodazole (chemistry, pharmacology)
• Small Molecule Libraries (chemistry, pharmacology)
• Sterol 14-Demethylase (metabolism)