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Evaluation of caspofungin resistance through the characterization of transcription factor deletion library, in Aspergillus fumigatus

Grant number: 12/24688-9
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2013
Effective date (End): December 31, 2016
Field of knowledge:Biological Sciences - Microbiology
Principal Investigator:Gustavo Henrique Goldman
Grantee:Jéssica Chiaratto
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Aspergillus fumigatus is a saprophytic fungus and a major opportunistic pathogen of mammals. Their conidia are inhaled into the lungs where they germinate and become active, resulting in a disease known as aspergillosis. Aspergillosis presents a serious health risk, especially to immunocompromised individuals. The most severe form of the disease is invasive aspergillosis. In opportunistic fungi such as A. fumigatus, some of the most important genetic components for the establishment of infection are transcription factors that can activate different programs which regulated virulence and pathogenicity. Echinocandins (caspofungin, anidulafungin, and micafungin) are antifungal agents that target the fungal cell wall. These agents reduce the total concentration of 1,3-²-D-glucan in the cell wall by inhibiting the activity of glucan synthase, resulting in hyphae morphological defects. The decreased concentration of 1,3-²-D-glucan can lead to a compensatory increase of chitin in the cell walls, allowing the cell to escape lethality. This phenomenon is called a paradoxical effect and represents an attenuation of the echinocandins activity in high concentrations. It is known that chitin production is made by Chs enzymes and the increase in the compensatory mechanism of chitin production is at least partially regulated by calcineurin. In A. fumigatus, only caspofungin is able to generate the paradoxical effect. However, caspofungin has an excellent safety profile and it has been increasingly used as second-line therapy against invasive aspergillosis. The composition, architecture, and biosynthetic mechanisms of the fungal cell wall have great importance for understanding the pathogenesis of invasive aspergillosis. Due to their role in cellular protection and hyphae growth, synthesis inhibition of cell components may be an important target against infections caused by A. fumigatus. (AU)

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