Project Lead(s): Leah Cowen
Fungi infect billions and kill at least 1.5 million people per year, a toll on par with tuberculosis or malaria.
Fungal infections are on the rise, due to the increase in AIDS and other conditions that compromise immune function, and there is urgent need for novel therapeutics.
The project team sought to establish the therapeutic potential of targeting the molecular chaperone Hsp90 to treat life-threatening fungal infections.
Proof of concept would be evaluated by:
1) Demonstrating that Hsp90 inhibitors abolish antifungal drug resistance of Indian clinical isolates, and enhance antifungal efficacy against biofilms;
2) Establishing that Hsp90 inhibitors transform antifungals from ineffective to highly effective against biofilm infections in a mammalian model;
3) Discovering a fungal-selective Hsp90 inhibitor; and
4) Demonstrating that the fungal-selective Hsp90 inhibitor enhances antifungal efficacy in a murine systemic infection model.
This would enable Phase II to bring the innovation to scale with clinical trials, development and deployment.
Significant progress was made in the steps to establish this novel therapeutic strategy for treating fungal infections that would be inexpensive to implement on a global scale. The strategy has broad therapeutic potential against species of Candida, Cryptococcus and Aspergillus, which cause life-threatening infections.
The team has demonstrated that the Hsp90 inhibitor radicicol, in combination with the azole fluconazole, can completely sterilize an infected catheter in a rat central venous catheter model of C. albicans biofilm infection.
The second key achievement of the project was the development of the first fungal-selective Hsp90 inhibitor.
Elements of the work have been presented at the University of Massachusetts Medical School, Genentech, the International Union of Microbiological Societies, and the International Conference on the Hsp90 Chaperone Machine.