Regulation of Drug Resistance Genes in C. Albicans
Principal Investigator: Carol Kumamoto
Abstract: [unreadable] DESCRIPTION (provided by applicant): [unreadable] This research project investigates the regulation of drug resistance genes in Candida albicans. Greater than 90% of AIDS patients suffer from oropharyngeal candidiasis (OPC). Fluconazole is the most commonly prescribed antifungal drug for these infections due to its efficacy and lack of side effects. Treatment failures with fluconazole have risen, most notably in AIDS patients with recurrent OPC that receive extended fluconazole therapy. The majority of treatment failures are due to fluconazole resistant C. albicans isolates. Although resistant C. albicans strain most often exhibit increased drug efflux due to the increased transcription of multidrug resistance pumps, little is known concerning the molecular mechanisms that lead to this increased transcription. C. aibicans drug resistant mutants have been isolated that increase transcription of the multidrug efflux pumps MDR1 and CDR2. These mutations fall into two classes: (i) transacting mutations that lead to high level expression of either MDR1 or CDR2, and (ii) cis-acting promoter mutations that lead to a more moderate, fluconazole-dependent increase in the transcription of either MDR1 or CDR2. The proposed research will analyze these mutations at the molecular level, determine the mechanisms that lead to increased transcription of these drug resistance pumps, and study the influence of drug selection regimens on the acquisition of these mutations. The long-term goal of these studies is to contribute to a more informed use of fluconazole with respect to prophylaxis, drug dosage regimens and the development of fluconazole resistant strains. [unreadable] [unreadable] [unreadable]
Funding Period: 2003-03-15 - 2009-02-28
more information: NIH RePORT
- An MDR1 promoter allele with higher promoter activity is common in clinically isolated strains of Candida albicansIgor Bruzual
Department of Molecular Biology and Microbiology, Tufts University, 136 Harrison Ave, Boston, MA, 02111, USA
Mol Genet Genomics 286:347-57. 2011..Through this mechanism, higher activity alleles of the MDR1 promoter could promote the development of drug resistance...
- Candida albicans biofilms produce antifungal-tolerant persister cellsMichael D LaFleur
Department of Biology, Northeastern University, 360 Huntington Ave, 134 Mugar Hall, Boston, MA 02115, USA
Antimicrob Agents Chemother 50:3839-46. 2006..It remains to be seen whether attachment initiates dormancy that leads to the formation of fungal persisters. This study suggests that persisters may be largely responsible for the multidrug tolerance of fungal biofilms...
- Transcriptional regulation of MDR1, encoding a drug efflux determinant, in fluconazole-resistant Candida albicans strains through an Mcm1p binding sitePerry J Riggle
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA
Eukaryot Cell 5:1957-68. 2006..Thus, the general transcription factor Mcm1p participates in the regulation of MDR1 expression...
- Biofilm formation by fluconazole-resistant Candida albicans strains is inhibited by fluconazoleIgor Bruzual
Department of Molecular Biology and Microbiology, Tufts University, 136 Harrison Ave, Boston, MA 02111, USA
J Antimicrob Chemother 59:441-50. 2007..The aim of this study was to determine the effect of the addition of the azole antifungal fluconazole on the initiation of biofilm formation by both drug-susceptible and drug-resistant C. albicans strains...