Candida albicans, an opportunistic pathogen, can cause vaginal, oral and lung infections in immunocompromised individuals and systemic tissue damages in acquired immunodeficiency patients. The chemotherapy of C. albicans infections is limited because of the strong similarities between C. albicans cells and human cells. However, the mitotic spindles in mammalian and Candida cells are constructed differently. In addition, significant differences exist in the sequences of fungal and mammalian tubulins, which are the building block units of mitotic spindles. Little information is available at biochemical and functional levels about Candida tubulin, and virtually nothing is known regarding the polymerization and dynamics properties of Candida microtubules. The thinking is that understanding the differences between fungal cell tubulin and mammalian tubulin could lead to development of new and selective drugs for the treatment of fungal diseases. Therefore, it is proposed to develop a large-scale purification strategy for C. Albicans tubulin based upon previous success in this laboratory with tubulin from Saccharomyces cerevisiae. The tubulin will be characterized biochemically, and the polymerization and dynamic properties of Candida microtubules determined. Finally, the mechanism of interaction of two known microtubule-targeted antifungal drugs (benomyl and griseofulvin) with the Candida tubulin will be determined and the mechanisms by which the drugs modulate the polymerization and dynamics properties of the tubulin will be elucidated.
| Panda, Dulal; Rathinasamy, K; Santra, Manas K et al. (2005) Kinetic suppression of microtubule dynamic instability by griseofulvin: implications for its possible use in the treatment of cancer. Proc Natl Acad Sci U S A 102:9878-83 |
| Gupta, Kamlesh; Bishop, Jamie; Peck, Austin et al. (2004) Antimitotic antifungal compound benomyl inhibits brain microtubule polymerization and dynamics and cancer cell proliferation at mitosis, by binding to a novel site in tubulin. Biochemistry 43:6645-55 |
