I gained my expertise in the molecular genetics and biology of fungi from my graduate training at the University of New England (Australia), utilizing the filamentous fungus Aspergillus nidulans as a model organism. Following the completion of my doctorate degree, I then started my postdoctoral training at the Univ. of Texas HSC San Antonio and Audie L. Murphy VAMC, South Texas VA Healthcare System under the mentorship of Samuel Lee, M.D., Ph.D. where I gained expertise in the study of Candida molecular pathogenesis and biofilm formation. In my first year, I was selected to be one of two recipients of the NIH CO-STAR institutional T32 training grant. Further demonstrating my commitment to the study of Candida pathogenesis, I gave up my position on the NIH T32 training grant at UTHSCSA for the next year in order to relocate with my mentor, Dr. Samuel Lee, who accepted the position of Section Chief, Infectious Diseases at Raymond G. Murphy VAMC, New Mexico Veterans Healthcare System (NMVAHCS). Continuing my research on C. albicans pathogenesis with Dr. Samuel Lee, I was the recipient of one of two UNM CIDI IDIP NIH T32 Post-doctoral Training Awards (2011-2013).
My current research interests cover two basic research areas of importance in Candida pathogenesis. The first stems from my postdoctoral work on Candida secretion. We have previously described the unique characteristic of the C. albicans pep12∆ mutant biofilm which detaches from the surface on which it has grown. The long-term goal of this project is directed at understanding the mechanism behind this instability which can lead to the identification of novel virulence-targets and subsequent development of antibiofilm therapeutic strategies. We thus performed transcriptional profiling of the pep12∆ mutant biofilm to identify genes that are differentially regulated during biofilm growth and identified uncharacterized genes of interest. The primary goal of the project is thus to elucidate both the specific mechanistic roles of these genes and their potential as therapeutic targets. The second project builds on my skillsets acquired as a graduate student working on carbon catabolite repression and its role in control of secretion of degradative enzymes in fungi. Specifically, the project aims to determine the role of the methionine/sulfur assimilation/utilization pathway in Candida albicans pathogenesis and gut commensalism. The role of carbon metabolism in C. albicans pathogenesis has been established, but how the organism responds to limited sources of other nutrients has yet to be examined. Without question, sulfur is an indispensable element to living organisms, as sulfur-containing metabolites are needed for growth and other cellular processes (e.g., methylation, protein synthesis). Notably, almost all translation of proteins from the RNA template initiate with a methionine moiety, a number of proteins utilize cysteine at functional catalytic sites and for maintaining structural integrity, and the sulfur-containing cofactor, coenzyme A, is important for many cellular oxidative and biosynthetic reactions. Further, the fungal methionine synthase has long been regarded as an attractive drug target as it is distinct from the mammalian homologue in terms of structure and function, with the latter requiring the co-factor cobalamin.
A third area of research interest concerns translational work. Specifically, using Candida albicans as a model opportunistic fungal pathogen, this project seeks to address the growing problem of poor response to antifungal therapy encountered in the clinical setting. Our goal is to identify compounds that can specifically inhibit the expression of CDR1 which encodes a major fungal plasma membrane efflux pump that plays a dominant role in fungal resistance to azole drugs. In a CTSC-funded pilot study, we identified (1) a small-molecule, specific repressor of CDR1 expression, which (2) was able to enhance the efficacy of fluconazole against azole-resistant clinical isolates. Next steps in this project include testing the generalizability of this treatment approach to other fungal infections, such as those caused by C. glabrata and C. krusei -- isolates that are innately resistant to azoles. Future grant proposals will also include elucidation of the mechanism-of-action of this compound and testing in both the in vivo models of disseminated candidiasis and rat-catheter biofilm to test their efficacy in combination with fluconazole, prior to pursuit of a small-scale clinical trial in human subjects.