JAC Advance Access published online on June 16, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh336
© 2004 by The British Society for Antimicrobial Chemotherapy
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1 Departments of Pharmacy, University of Tennessee Health Science Center, Memphis, TN USA; Children's Foundation Research Center, Le Bonheur Children's Medical Center, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: drogers{at}utmem.edu.
Objectives: The aim of this study was to identify changes in the gene expression profile of Candida albicans associated with the acquisition of experimentally induced resistance to amphotericin B and fluconazole. Methods: C. albicans SC5314 was passed in increasing concentrations of amphotericin B to generate isolate SC5314-AR. Susceptibility testing by Etest revealed SC5314-AR to be highly resistant to both amphotericin B and fluconazole. The gene expression profile of SC5314-AR was compared with that of SC5314 using DNA microarray analysis. Sterol composition was determined for both strains. Results: Upon examination of MICs of antifungal compounds, it was found that SC5314-AR was resistant to both amphotericin B and fluconazole. By microarray analysis a total of 134 genes were found to be differentially expressed, that is up-regulated or down-regulated by at least 50%, in SC5314-AR. In addition to the cell stress genes DDR48 and RTA2, the ergosterol biosynthesis genes ERG5, ERG6 and ERG25 were up-regulated. Several histone genes, protein synthesis genes and energy generation genes were down-regulated. Sterol analysis revealed the prevalence of sterol intermediates eburicol and lanosterol in SC5314-AR, whereas ergosterol was the predominant sterol in SC5314. Conclusion: Along with changes in expression of these ergosterol biosynthesis genes was the accumulation of sterol intermediates in the resistant strain, which would account for the decreased affinity of amphotericin B for membrane sterols and a decreased requirement for lanosterol demethylase activity in membrane sterol production. Furthermore, other genes are implicated as having a potential role in the polyene and azole antifungal resistant phenotype.
Revised May 6, 2004
Accepted May 25, 2004
Original article
Genome-wide expression profiling reveals genes associated with amphotericin B and fluconazole resistance in experimentally induced antifungal resistant isolates of Candida albicans
2 Departments of Pharmacy, University of Tennessee Health Science Center, Memphis, TN USA
3 Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, TX, USA
4 Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
5 Department of Drug Disposition, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN, USA
6 Departments of Pharmacy, University of Tennessee Health Science Center, Memphis, TN USA; Pharmaceutical Sciences, College of Pharmacy, Memphis, TN, USA; Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA; Children's Foundation Research Center, Le Bonheur Children's Medical Center, Memphis, TN, USA
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