Drug resistance modulation in yeast
Abstract number: P1362
Subik J., Sidorova M., Dzugasova V., Borecka S., Cernicka J., Kozovska Z., Hikkel I.
Objectives: Multidrug resistance is a defence mechanism used by cells to cope with rapidly changing growth and stress conditions, allowing them to survive in the presence of toxic compounds. In Saccharomyces cerevisiae and pathogenic Candida sp. the multidrug resistance is caused by an increased drug efflux by overexpressed membrane transporters due to gain-of-function mutations in transcription factors involved in the control of their expression. This work was aimed at the development of new strategies to reverse the drug resistance in yeast using S. cerevisiae and C. albicans as models.
Methods: Drug susceptibilities were determined by microbroth dilution method in 96-well plates according to the proposed NCCLS M27-A standard guidelines, by agar diffusion method or by spot assay. Loss-of-function pdr3 mutants in the genetic background of the S. cerevisiae strain ZK111 were selected on minimal medium containing galactose. The DNA sequence was determined with the ABI Prism 3100 DNA sequencer. Accumulation of rhodamine 6G was measured by flow cytometry.
Results: In this work we show that the susceptibility to antifungals of drug resistant and drug sensitive yeast cells can be enhanced by several ways. They involve: 1. The use of multicopy suppressors of drug resistance generated by loss-of-function mutations in genes encoding multidrug resistance transcriptional activators. 2. The inactivation of histone deacetylases associated with the chromatin remodeling. 3. The use of chemosensitising agents altering the lipid composition of yeast membranes.
Conclusion: The genetic and biochemical approaches to modulate multidrug resistance in yeast cells may prove useful in development of new strategies to combat fungal infections caused by drug resistant pathogens.
|Session name:||18th European Congress of Clinical Microbiology and Infectious Diseases|
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