An Antifungal Benzimidazole Derivative Inhibits Ergosterol Biosynthesis and Reveals Novel Sterols

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,...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2015-10, Vol.59 (10), p.6296-6307
Main Authors: Keller, Petra, Müller, Christoph, Engelhardt, Isabel, Hiller, Ekkehard, Lemuth, Karin, Eickhoff, Holger, Wiesmüller, Karl-Heinz, Burger-Kentischer, Anke, Bracher, Franz, Rupp, Steffen
Format: Article
Language:English
Subjects:
Antifungal Agents
Antifungal Agents - chemistry
Antifungal Agents - pharmacology
Benzimidazoles
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Candida - drug effects
Candida - growth & development
Candida - metabolism
Candida albicans - drug effects
Candida albicans - growth & development
Candida albicans - metabolism
Candida glabrata - drug effects
Candida glabrata - growth & development
Candida glabrata - metabolism
Ergosterol
Ergosterol - analogs & derivatives
Ergosterol - antagonists & inhibitors
Ergosterol - biosynthesis
Ergosterol - isolation & purification
Fluconazole
Fluconazole - chemistry
Fluconazole - pharmacology
Fungal Proteins - antagonists & inhibitors
Fungal Proteins - metabolism
High-Throughput Screening Assays
Mechanisms of Action: Physiological Effects
Nocodazole
Nocodazole - chemistry
Nocodazole - pharmacology
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Sterol 14-Demethylase
Sterol 14-Demethylase - metabolism
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Summary: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.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00640-15