1a. Objectives (from AD-416)
To verify antifungal chemosensitizing agents discovered in in vitro bioassays are also functional in a mammalian animal model system using BALB/c mice.
1b. Approach (from AD-416)
Chemosensitizing agents will be determined by PMR scientists using standard in vitro (Petri dish, microtitre plate) bioassays. These assays will include commercial antifungal agents co-applied with candidate chemosensitizing agents. A number of fungi pathogenic to animals and humans will be included such as Aspergillus flavus, A. fumigatus, A. terreus and Candida species and Cryptococcus neoformans. Agents found to be effective under in vitro assays will be provided to a collaborator at Montana State University. Animal testing will use neutropenic mice, BALB/c. The mice are treated with cyclophosphamide i. p. prior to infection, then with antifungal drug and chemosensitizing agent. The mice will be infected, nasally. The following day, treatments will be administered in five cohorts, a Tween control, one receiving only fungi, one receiving only antifungal drug, one receiving only chemosensitizing agent and one will receive both antifungal drug and chemosensitizer.
3. Progress Report
The research under this SCA is on chemosensitization for enhancing antifungal drug efficacy. This SCA takes the work from in vitro laboratory experiments to testing, in vivo, in mouse models to determine successful combinations of natural products and antifungal drugs to improve survivability of mice infected with an invasive fungal disease of the organs, especially the lungs, called aspergillosis. The ADODR is updated on progress of this study by phone calls, email exchanges, copies of internal data spreadsheets, as the need occurs. Research results obtained since last progress report include follow-up experiments with new batches of mice. Because this work involves live animals, appropriate procedures for humane treatment is followed by MSA vet school mandates. Follow-up studies are performed judiciously. From results, to date, it appears combinations of thymol (a natural product of the spice, thyme) and fluconazole improve survivability of the mice.