| Grant number: | 12/02920-7 |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| Effective date (Start): | September 01, 2012 |
| Effective date (End): | December 31, 2015 |
| Field of knowledge: | Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms |
| Principal Investigator: | Ana Lucia Fachin Saltoratto |
| Grantee: | Tamires Aparecida Bitencourt |
| Host Institution: | Universidade de Ribeirão Preto (UNAERP). Campus Ribeirão Preto. Ribeirão Preto , SP, Brazil |
Abstract The dermatophyte Trichophyton rubrum (T.rubrum) is the most frequent causative agent of superficial dermatomycoses in Brazil and worldwide. The dermatophytes are adapted to grown in the nail, skin and hair by using a variety of host proteins (particularly keratin) as a nutrient. To understand the complex interaction with the fungal host may identify genes differentially expressed by microarray simulating the infection of human skin by using a minimum culture medium including keratin (superficial infection) or elastin (deep infection) as a source of protein. Moreover, despite the importance of fungal infections, only a limited number of antifungal drugs currently available on the market due to lack of appropriate targets, since some are also very toxic to humans. Among the new molecular approaches, microarray tool may be useful to get an overview of the effects mediated by new antifungal drugs with different targets. Recent evidence suggests that the enzyme fatty acid synthase (FAS) catalyzes the synthesis of fatty acid, has great potential as new target antifungal The chalcones are flavonoids produced by plants and are natural inhibitors of FAS and present several interesting biological activities mainly antibacterial and antifungal activity (for example, MIC 12-18 mg / mL against Microsporum canis, and T.mentagrophytes T.rubrum). The study of natural inhibitors of FAS was the aim of our research group (Case 2009/12419-0 FAPESP), and the transchalcona showed antifungal activity against T.rubrum much more pronounced (MIC of 7.5 mg / ml) than controls used, fluconazole (MIC = 63¼g/ml) and the fatty acid synthase inhibitor Cerulenin (MIC = 125¼g/ml). Regarding the mechanism of action transchalcona reduced the ergosterol content and regeneration of protoplasts, showing that it damages the membrane. Furthermore, in experiments in quantitative PCR (real time) the transchalcona repressed gene FAS1 ERG6 gene and involved in fatty acid synthesis and ergosterol, respectively. These results showed that transchalcona is promising for the development of new antifungal agents, because this compound to act on several targets in the cell, interfering with cell wall, fatty acid and ergosterol synthesis. The aim of this project is to evaluated the transcriptional profile by microarray in T.rubrum in presence of transchalcona in culture conditions that mimic infection (minimal medium supplemented with keratin and elastin). Moreover, after validation, null mutants for some genes involved in drug and infection response will be constructed by gene disruption or RNA Interference in order to prove its functionality. | |
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