SBIR-STTR Award

There is an increasing incidence of life-threatening systemic fungal infections due to Candida species. Although fluconazole is currently the most widely used drug for preventing and treating these infections, its effectiveness is compromised, not only by the fact that it is fungistatic, but also by the recent emergence of fluconazole-resistant Candida strains. The therapeutic options for treating fluconazole-resistant Candida infections are limited to drugs with severe toxicity. In this project we plan to test the feasibility of developing an improved antifungal agent by potentiating the activity of fluconazole. A chemical library will be screened, first, for compounds which exhibit fungicidal activity in combination with fluconazole and, second, for compounds potentiating fluconazole activity in strains exhibiting intrinsic or acquired fluconazole resistance mechanisms. Preliminary screening of a portion of this library has already identified a promising candidate potentiator. The potentiating effects of the identified compounds will be quantitated and characterized and preliminary toxicity testing and structure activity analysis will be performed.The combination of fluconazole with a potentiator of its activity could form a powerful combination antifungal agent and extend the therapeutic options currently available for treating Candida infections. PROPOSED COMMERCIAL APPLICATIONS: The envisioned commercial product is a combination of fluconazole with a drug which potentiates its antifungal activity. Such a combination drug would have a major impact on the therapeutic and prophylactic treatment options for systemic Candida infections.

Thesaurus Terms:
Candida, antifungal agent, drug design /synthesis /production, drug screening /evaluation, fluconazole chemical registry /resource, chemical structure /function, drug adverse effect, drug interaction, drug resistance chemical synthesis

The goal of this Phase II SBIR project is to develop a clinically useful potentiator of the most widely used antifungal drugs, azoles. The major shortcoming of azole drugs is that they do not kill fungi but merely inhibit their growth. In fact, for the most medically important fungal pathogen, Candida albicans, this growth inhibition is only partial. The survival of the pathogen in the presence of the drug is the likely cause of the recurrence of fungal infections and emergence of azole resistance. Our Phase I studies identified two compounds in whose presence azoles become strongly fungicidal. These compounds show no antifungal activity on their own and no toxicity to human cells in culture. Structural derivatives of these two leads, displaying improved activity and pharmacological properties, will be obtained through intensive synthetic efforts. The biological activity of these derivatives will be thoroughly characterized in vitro. Their ability to improve antifungal activity of fluconazole will be tested in a murine model of systemic candidiasis. Finally, the molecular mechanism of action of the potentiators will be investigated in biochemical and genetic experiments. It is expected that the compounds developed in this project will significantly improve the improve the effectiveness of antifungal therapy. PROPOSED COMMERCIAL APPLICATION: The commercial product envisioned is a fungicidal combination of fluconazole with an adjuvant that potentiates antifungal activity. Such a product would have a major impact on the therapeutic and prophylactic treatment options for systemic Candida infections

Thesaurus Terms:
Candida albicans, antifungal agent, combination chemotherapy, drug design /synthesis /production, drug screening /evaluation, fluconazole candidiasis, disease /disorder model, drug interaction, multidrug resistance laboratory mouse