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

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

Antimicrob Agents Chemother. 2015 Jul 27;

Authors: Keller P, Müller C, Engelhardt I, Hiller E, Lemuth K, Eickhoff H, Wiesmüller KH, Burger-Kentischer A, Bracher F, Rupp S

Fungal infections are a leading cause of morbidity and mortality for hospitalized patients, mainly because they remain difficult to diagnose and treat. Disease ranges from widespread superficial infections like vulvovaginal infections to life-threatening systemic candidiasis. For systemic mycoses only a restricted arsenal of antifungals is available. Commonly used classes of antifungal compounds include azoles, polyenes and echinocandines. 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. This included C. glabrata and C. krusei, species which are highly resistant to antifungals. In this study, comparative analysis of EMC120B12 with fluconazole and nocodazole, using transcriptional profiling and sterol analysis strongly suggest 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, additional, hitherto unknown related sterols 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.

PMID: 26248360 [PubMed - as supplied by publisher]