Genomic Profiling of the Response of Candida Albicans to Itraconazole Treatment Using a DNA Microarray

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2001 May 17

PMID 11353609

Citations 79

Authors

M D De Backer

T Ilyina

X J Ma

S Vandoninck

W H Luyten

H Vanden Bossche

Affiliations

Soon will be listed here.

Abstract

The application of genome-wide expression profiling to determine how drugs achieve their therapeutic effect has provided the pharmaceutical industry with an exciting new tool for drug mode-of-action studies. We used DNA chip technology to study cellular responses to perturbations of ergosterol biosynthesis caused by the broad-spectrum antifungal agent itraconazole. Simultaneous examination of over 6,600 Candida albicans gene transcript levels, representing the entire genome, upon treatment of cells with 10 microM itraconazole revealed that 296 genes were responsive. For 116 genes transcript levels were decreased at least 2.5-fold, while for 180 transcript levels were similarly increased. A global upregulation of ERG genes in response to azole treatment was observed. ERG11 and ERG5 were found to be upregulated approximately 12-fold. In addition, a significant upregulation was observed for ERG6, ERG1, ERG3, ERG4, ERG10, ERG9, ERG26, ERG25, ERG2, IDII, HMGS, NCP1, and FEN2, all of which are genes known to be involved in ergosterol biosynthesis. The effects of itraconazole on a wide variety of known metabolic processes are discussed. As over 140 proteins with unknown function were responsive to itraconazole, our analysis might provide-in combination with phenotypic data-first hints of their potential function. The present report is the first to describe the application of DNA chip technology to study the response of a major human fungal pathogen to drug treatment.

Citing Articles

Transcriptional Reprogramming of in Response to Isoespintanol Treatment.

Contreras-Martinez O, Angulo-Ortiz A, Santafe-Patino G, Avina-Padilla K, Velasco-Pareja M, Yasnot M J Fungi (Basel). 2023; 9(12).

PMID: 38132799 PMC: 10744401. DOI: 10.3390/jof9121199.

Genome-wide translational response of to fluconazole treatment.

Choudhary S, Mundodi V, Smith A, Kadosh D Microbiol Spectr. 2023; :e0257223.

PMID: 37610232 PMC: 10580883. DOI: 10.1128/spectrum.02572-23.

Newly Discovered Antimicrobial Peptide Scyampcin from Scylla paramamosain Exhibits a Multitargeted Candidacidal Mechanism and Is Effective in a Murine Model of Vaginal Candidiasis.

Zhou Y, Meng X, Chen F, Xiong M, Zhang W, Wang K Antimicrob Agents Chemother. 2023; 67(6):e0002223.

PMID: 37162345 PMC: 10269043. DOI: 10.1128/aac.00022-23.

Study on the anti-biofilm mechanism of 1,8-cineole against species complex.

Zhang Y, Wang Y, Zhao X, Liu L, Xing R, Song X Front Pharmacol. 2022; 13:1010593.

PMID: 36330094 PMC: 9624185. DOI: 10.3389/fphar.2022.1010593.

Multi-site fungicides suppress banana Panama disease, caused by Fusarium oxysporum f. sp. cubense Tropical Race 4.

Cannon S, Kay W, Kilaru S, Schuster M, Gurr S, Steinberg G PLoS Pathog. 2022; 18(10):e1010860.

PMID: 36264855 PMC: 9584521. DOI: 10.1371/journal.ppat.1010860.

References

Marichal P, Gorrens J, Laurijssens L, Vermuyten K, Van Hove C, Le Jeune L . Accumulation of 3-ketosteroids induced by itraconazole in azole-resistant clinical Candida albicans isolates. Antimicrob Agents Chemother. 1999; 43(11):2663-70. PMC: 89540. DOI: 10.1128/AAC.43.11.2663. View

Lamb D, Maspahy S, Kelly D, Manning N, Geber A, Bennett J . Purification, reconstitution, and inhibition of cytochrome P-450 sterol delta22-desaturase from the pathogenic fungus Candida glabrata. Antimicrob Agents Chemother. 1999; 43(7):1725-8. PMC: 89351. DOI: 10.1128/AAC.43.7.1725. View

Kontoyiannis D, Sagar N, Hirschi K . Overexpression of Erg11p by the regulatable GAL1 promoter confers fluconazole resistance in Saccharomyces cerevisiae. Antimicrob Agents Chemother. 1999; 43(11):2798-800. PMC: 89564. DOI: 10.1128/AAC.43.11.2798. View

Rosamond J, Allsop A . Harnessing the power of the genome in the search for new antibiotics. Science. 2000; 287(5460):1973-6. DOI: 10.1126/science.287.5460.1973. View

Bammert G, Fostel J . Genome-wide expression patterns in Saccharomyces cerevisiae: comparison of drug treatments and genetic alterations affecting biosynthesis of ergosterol. Antimicrob Agents Chemother. 2000; 44(5):1255-65. PMC: 89853. DOI: 10.1128/AAC.44.5.1255-1265.2000. View

Harousseau J, Dekker A, Stamatoullas-Bastard A, Fassas A, Linkesch W, Gouveia J . Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B. Antimicrob Agents Chemother. 2000; 44(7):1887-93. PMC: 89980. DOI: 10.1128/AAC.44.7.1887-1893.2000. View

Henry K, Nickels J, Edlind T . Upregulation of ERG genes in Candida species by azoles and other sterol biosynthesis inhibitors. Antimicrob Agents Chemother. 2000; 44(10):2693-700. PMC: 90137. DOI: 10.1128/AAC.44.10.2693-2700.2000. View

Parks L . Metabolism of sterols in yeast. CRC Crit Rev Microbiol. 1978; 6(4):301-41. DOI: 10.3109/10408417809090625. View

VAN DEN BOSSCHE H, Willemsens G, Cools W, Marichal P, Lauwers W . Hypothesis on the molecular basis of the antifungal activity of N-substituted imidazoles and triazoles. Biochem Soc Trans. 1983; 11(6):665-7. DOI: 10.1042/bst0110665. View

10.

Vanden Bossche H, Willemsens G, Marichal P . Anti-Candida drugs--the biochemical basis for their activity. Crit Rev Microbiol. 1987; 15(1):57-72. DOI: 10.3109/10408418709104448. View

11.

Vanden Bossche H . Biochemical targets for antifungal azole derivatives: hypothesis on the mode of action. Curr Top Med Mycol. 1985; 1:313-51. DOI: 10.1007/978-1-4613-9547-8_12. View

12.

Mbaya B, Fegueur M, Servouse M, Karst F . Regulation of squalene synthetase and squalene epoxidase activities in Saccharomyces cerevisiae. Lipids. 1989; 24(12):1020-3. DOI: 10.1007/BF02544072. View

13.

Turi T, Loper J . Multiple regulatory elements control expression of the gene encoding the Saccharomyces cerevisiae cytochrome P450, lanosterol 14 alpha-demethylase (ERG11). J Biol Chem. 1992; 267(3):2046-56. View

14.

Fonzi W, Irwin M . Isogenic strain construction and gene mapping in Candida albicans. Genetics. 1993; 134(3):717-28. PMC: 1205510. DOI: 10.1093/genetics/134.3.717. View

15.

Vanden Bossche H, Marichal P, Le Jeune L, Coene M, Gorrens J, Cools W . Effects of itraconazole on cytochrome P-450-dependent sterol 14 alpha-demethylation and reduction of 3-ketosteroids in Cryptococcus neoformans. Antimicrob Agents Chemother. 1993; 37(10):2101-5. PMC: 192235. DOI: 10.1128/AAC.37.10.2101. View

16.

Truan G, Epinat J, Rougeulle C, Cullin C, Pompon D . Cloning and characterization of a yeast cytochrome b5-encoding gene which suppresses ketoconazole hypersensitivity in a NADPH-P-450 reductase-deficient strain. Gene. 1994; 142(1):123-7. DOI: 10.1016/0378-1119(94)90366-2. View

17.

Marbois B, Clarke C . The COQ7 gene encodes a protein in saccharomyces cerevisiae necessary for ubiquinone biosynthesis. J Biol Chem. 1996; 271(6):2995-3004. DOI: 10.1074/jbc.271.6.2995. View

18.

Marcireau C, Joets J, Pousset D, Guilloton M, Karst F . FEN2: a gene implicated in the catabolite repression-mediated regulation of ergosterol biosynthesis in yeast. Yeast. 1996; 12(6):531-9. DOI: 10.1002/(SICI)1097-0061(199605)12:6%3C531::AID-YEA934%3E3.0.CO;2-E. View

19.

Smith S, CROWLEY J, Parks L . Transcriptional regulation by ergosterol in the yeast Saccharomyces cerevisiae. Mol Cell Biol. 1996; 16(10):5427-32. PMC: 231542. DOI: 10.1128/MCB.16.10.5427. View

20.

Sanglard D, Ischer F, Monod M, Bille J . Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob Agents Chemother. 1996; 40(10):2300-5. PMC: 163524. DOI: 10.1128/AAC.40.10.2300. View