title: A screening assay based on host-pathogen interaction models identifies a set of novel antifungal benzimidazole derivatives.
abstract: Fungal infections are a serious health problem in clinics, especially in the immune-compromised patient. Disease ranges from widespread superficial infections like vulvovaginal infections to life-threatening systemic candidiasis. Especially for systemic mycoses, only a limited arsenal of antifungals is available. The most commonly used classes of antifungal compounds used include azoles, polyenes, and echinocandins. Due to emerging resistance to standard therapy, significant side effects, and high costs for several antifungals, there is a medical need for new antifungals in the clinic and general practice. In order to expand the arsenal of compounds with antifungal activities, we screened a compound library including more than 35,000 individual compounds derived from organic synthesis as well as combinatorial compound collections representing mixtures of compounds for antimycotic activity. In total, more than 100,000 compounds were screened using a new type of activity-selectivity assay, analyzing both the antifungal activity and the compatibility with human cells at the same time. One promising hit, an (S)-2-aminoalkyl benzimidazole derivative, was developed among a series of lead compounds showing potent antifungal activity. (S)-2-(1-Aminoisobutyl)-1-(3-chlorobenzyl) benzimidazole showed the highest antifungal activity and the best compatibility with human cells in several cell culture models and against a number of clinical isolates of several species of pathogenic Candida yeasts. Transcriptional profiling indicates that the newly discovered compound is a potential inhibitor of the ergosterol pathway, in contrast to other benzimidazole derivatives, which target microtubules.
authors: Fraunhofer Institute for Interfacial Engineering and Biotechnology, Nobelstr. 12, 70569 Stuttgart, Germany.
authors: Anke
authors: A
authors: Burger-Kentischer
authors: Doris
authors: D
authors: Finkelmeier
authors: Petra
authors: P
authors: Keller
authors: Jörg
authors: J
authors: Bauer
authors: Holger
authors: H
authors: Eickhoff
authors: Gerald
authors: G
authors: Kleymann
authors: Walid
authors: W
authors: Abu Rayyan
authors: Anurag
authors: A
authors: Singh
authors: Klaus
authors: K
authors: Schröppel
authors: Karin
authors: K
authors: Lemuth
authors: Karl-Heinz
authors: KH
authors: Wiesmüller
authors: Steffen
authors: S
authors: Rupp
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D016466:CHO Cells; D002175:Candida / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D002460:Cell Line; D006224:Cricetinae; D025141:Drug Resistance, Fungal; D004875:Ergosterol / Q000037:antagonists & inhibitors; D016681:Genome, Fungal; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D054884:Host-Pathogen Interactions / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D020411:Oligonucleotide Array Sequence Analysis; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: C568522:2-(1-aminoisobutyl)-1-(3-chlorobenzyl)benzimidazole; D000935:Antifungal Agents; D001562:Benzimidazoles; D004875:Ergosterol