An Antifungal Benzimidazole Derivative Inhibits Ergosterol Biosynthesis and Reveals Novel Sterols

被引:41
作者
Keller, Petra [1 ]
Mueller, Christoph [2 ]
Engelhardt, Isabel [1 ]
Hiller, Ekkehard [3 ]
Lemuth, Karin [1 ]
Eickhoff, Holger [4 ]
Wiesmueller, Karl-Heinz [4 ]
Burger-Kentischer, Anke [3 ]
Bracher, Franz [2 ]
Rupp, Steffen [1 ,3 ]
机构
[1] Univ Stuttgart, Inst Grenzflachenverfahrenstech & Plasmatechnol, D-70174 Stuttgart, Germany
[2] Univ Munich, Dept Pharm, Zentrum Pharmaforsch, Munich, Germany
[3] Fraunhofer Inst Grenzflachen & Bioverfahrenstech, Stuttgart, Germany
[4] EMC Microcollect GmbH, Tubingen, Germany
关键词
CANDIDA-ALBICANS; SACCHAROMYCES-CEREVISIAE; BOTRYTIS-CINEREA; SCREENING ASSAY; YEAST; FLUCONAZOLE; RESISTANCE; IDENTIFICATION; EPIDEMIOLOGY; SURVEILLANCE;
D O I
10.1128/AAC.00640-15
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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-3 beta,6 alpha-diol, indicating Erg11p inhibition, related sterols that were hitherto unknown accumulated in the cells during EMC120B12 treatment. The novel sterols have a 3 beta,6 alpha-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.
引用
收藏
页码:6296 / 6307
页数:12
相关论文
共 50 条
  • [1] Ergosterol biosynthesis pathway in Aspergillus fumigatus
    Alcazar-Fuoli, Laura
    Mellado, Emilia
    Garcia-Effron, Guillermo
    Lopez, Jordi R.
    Grimalt, Joan O.
    Cuenca-Estrella, J. Manuel
    Rodriguez-Tudela, Juan L.
    [J]. STEROIDS, 2008, 73 (03) : 339 - 347
  • [2] [Anonymous], CLIN MICROBIOL INFEC
  • [3] High-Throughput-Screening-Based Identification and Structure-Activity Relationship Characterization Defined (S)-2-(1-Aminoisobutyl)-1-(3-chlorobenzyl)benzimidazole as a Highly Antimycotic Agent Nontoxic to Cell Lines
    Bauer, Joerg
    Kinast, Stephan
    Burger-Kentischer, Anke
    Finkelmeier, Doris
    Kleymann, Gerald
    Abu Rayyan, Walid
    Schroepple, Klaus
    Singh, Anurag
    Jung, Guenther
    Wiesmueller, Karl-Heinz
    Rupp, Steffen
    Eickhoff, Holger
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (19) : 6993 - 6997
  • [4] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING
    BENJAMINI, Y
    HOCHBERG, Y
    [J]. JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) : 289 - 300
  • [5] Azasteroids as antifungals
    Burbiel, J
    Bracher, F
    [J]. STEROIDS, 2003, 68 (7-8) : 587 - 594
  • [6] A Screening Assay Based on Host-Pathogen Interaction Models Identifies a Set of Novel Antifungal Benzimidazole Derivatives
    Burger-Kentischer, Anke
    Finkelmeier, Doris
    Keller, Petra
    Bauer, Joerg
    Eickhoff, Holger
    Kleymann, Gerald
    Abu Rayyan, Walid
    Singh, Anurag
    Schroeppel, Klaus
    Lemuth, Karin
    Wiesmueller, Karl-Heinz
    Rupp, Steffen
    [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2011, 55 (10) : 4789 - 4801
  • [7] Activity of echinocandins and triazoles against a contemporary (2012) worldwide collection of yeast and moulds collected from invasive infections
    Castanheira, Mariana
    Messer, Shawn A.
    Jones, Messer Ronald N.
    Farrell, David J.
    Pfaller, Michael A.
    [J]. INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, 2014, 44 (04) : 320 - 326
  • [8] Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia
    Cornely, Oliver A.
    Maertens, Johan
    Winston, Drew J.
    Perfect, John
    Ullmann, Andrew J.
    Walsh, Thomas J.
    Helfgott, David
    Holowiecki, Jerzy
    Stockelberg, Dick
    Goh, Yeow-Tee
    Petrini, Mario
    Hardalo, Cathy
    Suresh, Ramachandran
    Angulo-Gonzalez, David
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2007, 356 (04) : 348 - 359
  • [9] Multiple hypothesis testing in microarray experiments
    Dudoit, S
    Shaffer, JP
    Boldrick, JC
    [J]. STATISTICAL SCIENCE, 2003, 18 (01) : 71 - 103
  • [10] EBERT E, 1983, Z NATURFORSCH C, V38, P28