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Antimicrobial Agents and Chemotherapy, May 2004, p. 1778-1787, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1778-1787.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Membrane Sphingolipid-Ergosterol Interactions Are Important Determinants of Multidrug Resistance in Candida albicans

Kasturi Mukhopadhyay,1,{dagger} Tulika Prasad,1,{dagger} Preeti Saini,1 Thomas J. Pucadyil,2 Amitabha Chattopadhyay,2 and Rajendra Prasad1*

Membrane Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067,1 Centre for Cellular and Molecular Biology, Hyderabad 500007, India2

Received 19 December 2003/ Accepted 5 January 2004

In this study, we examined the importance of membrane ergosterol and sphingolipids in the drug susceptibilities of Candida albicans. We used three independent methods to test the drug susceptibilities of erg mutant cells, which were defective in ergosterol biosynthesis. While spot and filter disk assays revealed that erg2 and erg16 mutant cells of C. albicans became hypersensitive to almost all of the drugs tested (i.e., 4-nitroquinoline oxide, terbinafine, o-phenanthroline, itraconazole, and ketoconazole), determination of the MIC at which 80% of the cells were inhibited revealed more than fourfold increase in susceptibility to ketoconazole and terbinafine. Treatment of wild-type C. albicans cells with fumonisin B1 resulted in 45% inhibition of sphingolipid biosynthesis and caused cells to become hypersensitive to the above drugs. Although erg mutants displayed enhanced membrane fluidity and passive diffusion, these changes alone were not sufficient to elicit the observed hypersusceptibility phenotype of erg mutants. For example, the induction in vitro of a 12% change in the membrane fluidity of C. albicans cells by a membrane fluidizer, benzyl alcohol, did not affect the drug susceptibilities of Candida cells. Additionally, the surface localization of green fluorescent protein-tagged Cdr1p, a major drug efflux pump protein of C. albicans, revealed that any disruption in ergosterol and sphingolipid interactions also interfered with its proper surface localization and functioning. A 50% reduction in the efflux of the Cdr1p substrate, rhodamine 6G, in erg mutant cells or in cells with a reduced sphingolipid content suggested a strong correlation between these membrane lipid components and this major efflux pump protein. Taken together, the results of our study demonstrate for the first time that there is an interaction between membrane ergosterol and sphingolipids, that a reduction in the content of either of these two components results in a disruption of this interaction, and that this disruption has deleterious effects on the drug susceptibilities of C. albicans cells.

* Corresponding author. Mailing address: Membrane Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India. Phone: 91-11-2670-4509. Fax: 91-11-2618-7338. E-mail: rp47{at}mail.jnu.ac.in.

{dagger} Kasturi Mukhopadhyay and Tulika Prasad contributed equally to this work.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1778-1787, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1778-1787.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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