An antifungal benzimidazole derivative inhibits ergosterol biosynthesis and reveals novel sterols

Antimicrobial Agents and Chemotherapy

Volumn 59, Issue 10, 2015, Pages 6296-6307

  Keller, Petra ^a   Müller, Christoph ^b   Engelhardt, Isabel ^a   Hiller, Ekkehard ^c   Lemuth, Karin ^a,e   Eickhoff, Holger ^d   Wiesmüller, Karl Heinz ^d   Burger Kentischer, Anke ^c   Bracher, Franz ^b   Rupp, Steffen ^a,c  

^a UNIVERSITY OF STUTTGART   (Germany)

^b UNIVERSITY OF MUNICH   (Germany)

^c FRAUNHOFER INSTITUTE FOR INTERFACIAL ENGINEERING AND BIOTECHNOLOGY IGB   (Germany)

^d EMC MICROCOLLECTIONS GMBH   (Germany)

^e ROBERT BOSCH GMBH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

14 METHYLERGOSTA 8,24(28) DIEN 3BETA,6ALPHA DIOL; 2 (1 AMINOISOBUTYL) 1 (3 CHLOROBENZYL)BENZIMIDAZOLE; ANTIFUNGAL AGENT; BENZIMIDAZOLE DERIVATIVE; ERGOSTEROL; FLUCONAZOLE; NOCODAZOLE; STEROL; UNCLASSIFIED DRUG; 14-METHYLERGOSTA-8,24(28)-DIEN-3,6-DIOL; FUNGAL PROTEIN; MOLECULAR LIBRARY; STEROL 14ALPHA DEMETHYLASE;

ARTICLE; BIOSYNTHESIS; CANDIDA GLABRATA; CANDIDA PARAPSILOSIS; CANDIDA TROPICALIS; CONTROLLED STUDY; DRUG MECHANISM; FUNGAL GENE; MASS SPECTROMETRY; NONHUMAN; PICHIA KUDRIAVZEVII; PRIORITY JOURNAL; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; CANDIDA; CANDIDA ALBICANS; CHEMISTRY; DRUG EFFECTS; GROWTH, DEVELOPMENT AND AGING; HIGH THROUGHPUT SCREENING; ISOLATION AND PURIFICATION; METABOLISM; MOLECULAR LIBRARY; PHARMACOLOGY;

ANTIFUNGAL AGENTS; BENZIMIDAZOLES; CANDIDA; CANDIDA ALBICANS; CANDIDA GLABRATA; ERGOSTEROL; FLUCONAZOLE; FUNGAL PROTEINS; HIGH-THROUGHPUT SCREENING ASSAYS; NOCODAZOLE; SMALL MOLECULE LIBRARIES; STEROL 14-DEMETHYLASE;

EID: 84942287920     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.00640-15     Document Type: Article

References (51)

1. Pfaller MA, Diekema DJ. 2007. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133-136. http://dx.doi.org/10.1128/CMR.00029-06.
2. Tortorano AM, Kibbler C, Peman J, Bernhardt H, Klingspor L, Grillot R. 2006. Candidaemia in Europe: epidemiology and resistance. Int J Antimicrob Agents 27:359-366. http://dx.doi.org/10.1016/j.ijantimicag.2006.01.002.
3. Castanheira M, Messer SA, Jones RN, Farrell DJ, Pfaller MA. 2014. Activity of echinocandins and triazoles against a contemporary (2012) worldwide collection of yeast and moulds collected from invasive infections. Int J Antimicrob Agents 44:320-326. http://dx.doi.org/10.1016/j.ijantimicag.2014.06.007.
4. Odds FC. 2010. Resistance to antifungal agents. Fungal Genet Biol 47:190. http://dx.doi.org/10.1016/j.fgb.2009.12.005.
5. Pfaller MA, Diekema DJ, Rinaldi MG, Barnes R, Hu B, Veselov AV, Tiraboschi N, Nagy E, Gibbs DL, Global Antifungal Surveillance Group. 2005. Results from the ARTEMIS DISK global antifungal surveillance study: a 6.5-year analysis of susceptibilities of Candida and other yeast species to fluconazole and voriconazole by standardized disk diffusion testing. J Clin Microbiol 43:5848-5859. http://dx.doi.org/10.1128/JCM.43.12.5848-5859.2005.
6. Karthaus M, Cornely OA. 2007. Treatment options in candidaemia. Mycoses 50:44-49. http://dx.doi.org/10.1111/j.1439-0507.2007.01379.x.
7. Pasqualotto AC, Denning DW. 2008. New and emerging treatments for fungal infections. J Antimicrob Chemother 61:i19-i30. http://dx.doi.org/10.1093/jac/dkm428.
8. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh Y, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D. 2007. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 356:348-359. http://dx.doi.org/10.1056/NEJMoa061094.
9. Ullmann AJ, Cornely OA, Donnelly JP, Akova M, Arendrup MC, Arikan-Akdagli S, Bassetti M, Bille J, Calandra T, Castagnola E, Garbino J, Groll AH, Herbrecht R, Hope WW, Jensen HE, Kullberg BJ, Lass-Florl C, Lortholary O, Meersseman W, Petrikkos G, Richardson MD, Roilides E, Verweij PE, Viscoli C, Cuenca-Estrella M. 2012. ESCMID∗ guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases. Clin Microbiol Infect 18(Suppl 7):1-8. http://dx.doi.org/10.1111/1469-0691.12037.
10. Bauer J, Kinast S, Burger-Kentischer A, Finkelmeier D, Kleymann G, Abu Rayyan W, Schropple K, Singh A, Jung G, Wiesmuller KH, Rupp S, Eickhoff H. 2011. 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. J Med Chem 54:6993-6997. http://dx.doi.org/10.1021/jm200571e.
11. Burger-Kentischer A, Finkelmeier D, Keller P, Bauer J, Eickhoff H, Kleymann G, Abu Rayyan W, Singh A, Schröppel K, Lemuth K, Wiesmüller KH, Rupp S. 2011. A screening assay based on host-pathogen interaction models identifies a set of novel antifungal benzimidazole derivatives. Antimicrob Agents Chemother 55:4789-4801. http://dx.doi.org/10.1128/AAC.01657-10.
12. Pfaller MA, Diekema DJ, Gibbs DL, Newell VA, Nagy E, Dobiasova S, Rinaldi M, Barton R, Veselov A, Global Antifungal Surveillance Group. 2008. Candida krusei, a multidrug-resistant opportunistic fungal pathogen: geographic and temporal trends from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005. J Clin Microbiol 46:515-521. http://dx.doi.org/10.1128/JCM.01915-07.
13. Li J, Katiyar SK, Edlind TD. 1996. Site-directed mutagenesis of Saccharomyces cerevisiae β-tubulin: interaction between residue 167 and benzimidazole compounds. FEBS Lett 385:7-10. http://dx.doi.org/10.1016/0014-5793(96)00334-1.
14. Kunkel W. 1980. Effects of the antimicrotubular cancerostatic drug nocodazole on the yeast Saccharomyces cerevisiae. Z Allg Mikrobiol 20:315-324. http://dx.doi.org/10.1002/jobm.3630200503.
15. Lupetti A, Danesi R, Campa M, Del Tacca M, Kelly S. 2002. Molecular basis of resistance to azole antifungals. Trends Mol Med 8:76-81. http://dx.doi.org/10.1016/S1471-4914(02)02280-3.
16. Müller C, Staudacher V, Krauss J, Giera M, Bracher F. 2013. A convenient cellular assay for the identification of the molecular target of ergosterol biosynthesis inhibitors and quantification of their effects on total ergosterol biosynthesis. Steroids 78:483-493. http://dx.doi.org/10.1016/j.steroids.2013.02.006.
17. Vanden Bossche H, Warnock DW, Dupont B, Kerridge D, Sengupta S, Improvisi L, Marichal P, Odds FC, Provost F, Ronin O. 1994. Mechanisms and clinical impact of antifungal drug resistance. J Med Vet Mycol 32:189-202. http://dx.doi.org/10.1080/02681219480000821.
18. Fonzi WA, Irwin MY. 1993. Isogenic strain construction and gene mapping in Candida albicans. Genetics 134:717-728.
19. Subcommittee on Antifungal Susceptibility Testing of the ESCMID European Committee for Antimicrobial Susceptibility Testing. 2008. EUCAST definitive document EDef 7.1: method for the determination of broth dilution MICs of antifungal agents for fermentative yeasts. Clin Microbiol Infect 14:398-405. http://dx.doi.org/10.1111/j.1469-0691.2007.01935.x.
20. Kilmartin JV, Adams AEM. 1984. Structural rearrangements of tubulin and actin during the cell-cycle of the yeast Saccharomyces. J Cell Biol 98:922-933. http://dx.doi.org/10.1083/jcb.98.3.922.
21. R Core Team. 2009. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.
22. Smyth GK. 2005. Limma: linear models for microarray data, p 397-420. In Gentleman R, Carey VJ, Huber W, Irizzary RA, Dudoit S (ed), Bioinformatics and computational biology solutions using R and Bioconductor. Springer, New York, NY.
23. Lönnstedt I, Speed TP. 2002. Replicated microarray data. Stat Sin 12:31-46.
24. Smyth GK. 2004. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3:Article 3.
25. Smyth GK, Michaud J, Scott HS. 2005. Use of within-array replicate spots for assessing differential expression in microarray experiments. Bioinformatics 21:2067-2075. http://dx.doi.org/10.1093/bioinformatics/bti270.
26. Ritchie ME, Silver J, Oshlack A, Holmes M, Diyagama D, Holloway A, Smyth GK. 2007. A comparison of background correction methods for two-colour microarrays. Bioinformatics 23:2700-2707. http://dx.doi.org/10.1093/bioinformatics/btm412.
27. Smyth GK, Speed T. 2003. Normalization of cDNA microarray data. Methods 31:265-273. http://dx.doi.org/10.1016/S1046-2023(03)00155-5.
28. Dudoit S, Popper Schaffer J, Boldrick JC. 2003. Multiple hypothesis testing in microarray experiments. Stat Sci 18:71-103. http://dx.doi.org/10.1214/ss/1056397487.
29. Benjamini Y, Hochberg Y. 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57:289-300.
30. Burbiel J, Bracher F. 2003. Azasteroids as antifungals. Steroids 68:587-594. http://dx.doi.org/10.1016/S0039-128X(03)00080-1.
31. Krauss J, Müller C, Kiessling J, Richter S, Staudacher V, Bracher F. 2014. Synthesis and biological evaluation of novel N-alkyl tetra- and decahydroisoquinolines: novel antifungals that target ergosterol biosynthesis. Arch Pharm (Weinheim) 347:283-290. http://dx.doi.org/10.1002/ardp.201300338.
32. Renard D, Perruchon J, Giera M, Muller J, Bracher F. 2009. Side chain azasteroids and thiasteroids as sterol methyltransferase inhibitors in ergosterol biosynthesis. Bioorg Med Chem 17:8123-8137. http://dx.doi.org/10.1016/j.bmc.2009.09.037.
33. Alcazar-Fuoli L, Mellado E, Garcia-Effron G, Lopez JF, Grimalt JO, Cuenca-Estrella JM, Rodriguez-Tudela JL. 2008. Ergosterol biosynthesis pathway in Aspergillus fumigatus. Steroids 73:339-347. http://dx.doi.org/10.1016/j.steroids.2007.11.005.
34. Kelly SL, Lamb DC, Corran AJ, Baldwin BC, Kelly DE. 1995. Mode of action and resistance to azole antifungals associated with the formation of 14α-methylergosta-8,24(28)-dien-3β,6α-diol. Biochem Biophys Res Commun 207:910-915. http://dx.doi.org/10.1006/bbrc.1995.1272.
35. Martel CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AGS, Kelly DE, Kelly SL. 2010. AclinicalisolateofCandida albicans with mutations in ERG11 (encoding sterol 14α-demethylase) and ERG5 (encoding C22 desaturase) is cross resistant to azoles and amphotericin B. Antimicrob Agents Chemother 54:3578-3583. http://dx.doi.org/10.1128/AAC.00303-10.
36. Nakanishi S, Nishino T, Nagai J, Katsuki H. 1987. Characterization of nystatin-resistant mutants of Saccharomyces cerevisiae and preparation of sterol intermediates using the mutants. J Biochem 101:535-544.
37. Osumi T, Taketani S, Katsuki H, Kuhara T, Matsumoto I. 1978. Ergosterol biosynthesis in yeast; pathways in the late stages and their variation under various conditions. J Biochem 83:681-691.
38. Shimokawa O, Kato Y, Kawano K, Nakayama H. 1989. Accumulation of 14α-methylergosta-8,24(28)-dien-3β,6α-diol in 14α-demethylation mutants of Candida albicans: genetic evidence for the involvement of 5-desaturase. Biochim Biophys Acta 1003:15-19. http://dx.doi.org/10.1016/0005-2760(89)90092-1.
39. Ebert E, Gaudin J, Muecke W, Ramsteiner K, Vogel C, Fuhrer H. 1983. Inhibition of ergosterol biosynthesis by etaconazole in Ustilago maydis.Z Naturforsch 38C:28-34.
40. Quail MA, Arnold A, Moore DJ, Goosey MW, Kelly SL. 1993. Ketoconazole-mediated growth inhibition in Botrytis cinerea and Saccharomyces cerevisiae. Phytochemistry 32:273-280. http://dx.doi.org/10.1016/S0031-9422(00)94980-X.
41. Griffiths KM, Bacic A, Howlett BJ. 2003. Sterol composition of mycelia of the plant pathogenic ascomycete Leptosphaeria maculans. Phytochemistry 62:147-153. http://dx.doi.org/10.1016/S0031-9422(02)00505-8.
42. Loeffler RST, Hayes AL. 1990. Sterols of the plant pathogenic fungi Botrytis cinerea and Pyrenophora teres. Phytochemistry 29:3423-3425. http://dx.doi.org/10.1016/0031-9422(90)85250-J.
43. Zheng WF, Liu T, Xiang XY, Gu Q. 2007. Sterol composition in field-grown and cultured mycelia of Inonotus obliquus. Yao Xue Xue Bao 42:750-756.
44. Giera M, Plossl F, Bracher F. 2007. Fast and easy in vitro screening assay for cholesterol biosynthesis inhibitors in the post-squalene pathway. Steroids 72:633-642. http://dx.doi.org/10.1016/j.steroids.2007.04.005.
45. 5,6-desaturation. FEBS Lett 400:80-82. http://dx.doi.org/10.1016/S0014-5793(96)01360-9.
46. Parks LW, Casey WM. 1995. Physiological implications of sterol biosynthesis in yeast. Annu Rev Microbiol 49:95-116. http://dx.doi.org/10.1146/annurev.mi.49.100195.000523.
47. Fryberg M, Unrau AM, Oehlschl AC. 1973. Biosynthesis of ergosterol in yeast: evidence for multiple pathways. J Am Chem Soc 95:5747-5757. http://dx.doi.org/10.1021/ja00798a051.
48. Stein SE, Babushok VI, Brown RL, Linstrom PJ. 2007. Estimation of Kovats retention indices using group contributions. J Chem Inf Model 47:975-980. http://dx.doi.org/10.1021/ci600548y.
49. Gassiot M, Fernandez E, Firpo G, Carbo R, Martin M. 1975. Empirical quantum chemical approach to structure-gas chromatographic retention index relationship. I. Sterol acetates. J Chromatogr 108:337-344. http://dx.doi.org/10.1016/S0021-9673(00)84677-4.
50. Gerst N, Ruan B, Pang J, Wilson WK, Schroepfer GJ, Jr. 1997. An updated look at the analysis of unsaturated C27 sterols by gas chromatography and mass spectrometry. J Lipid Res 38:1685-1701.
51. Fan J, Urban M, Parker JE, Brewer HC, Kelly SL, Hammond-Kosack KE, Fraaije BA, Liu X, Cools HJ. 2013. Characterization of the sterol 14α-demethylases of Fusarium graminearum identifies a novel genus-specific CYP51 function. New Phytol 198:821-835. http://dx.doi.org/10.1111/nph.12193.