? 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. ? ? ?
| Bruzual, Igor; Kumamoto, Carol A (2011) An MDR1 promoter allele with higher promoter activity is common in clinically isolated strains of Candida albicans. Mol Genet Genomics 286:347-57 |
| Bruzual, Igor; Riggle, Perry; Hadley, Susan et al. (2007) Biofilm formation by fluconazole-resistant Candida albicans strains is inhibited by fluconazole. J Antimicrob Chemother 59:441-50 |
| LaFleur, Michael D; Kumamoto, Carol A; Lewis, Kim (2006) Candida albicans biofilms produce antifungal-tolerant persister cells. Antimicrob Agents Chemother 50:3839-46 |
| Riggle, Perry J; Kumamoto, Carol A (2006) Transcriptional regulation of MDR1, encoding a drug efflux determinant, in fluconazole-resistant Candida albicans strains through an Mcm1p binding site. Eukaryot Cell 5:1957-68 |
