PI: Dr. Aimee E. Dudley
Location: Pacific Northwest Diabetes Resesarch Institute (PNDRI)
Development of antifungal compounds that target fungal biofilm formation
Opportunistic fungal pathogens pose a large and growing problem for the U.S. healthcare system.
“Antifungal therapy is limited by the small arsenal of drugs, toxicity, and the emergence of resistance. Moreover, the antifungal drug pipeline is mostly dry, so that no new antifungal drugs are expected to reach the market anytime soon.” (Pierce, CG and Lopez-Ribot, JL. (2013) Candidiasis drug discovery and development: new approaches targeting virulence for discovering and identifying new drugs. Expert opinion on drug discovery 8:1117-1126.)
Although antifungals have been available for over 50 years, the development of improved therapeutics has been stymied by the strong similarities between the cellular processes of yeast and mammalian cells. Commonly used drugs target just two cellular components, ergosterol in the plasma membrane and 1,3-beta-D-glucan in the cell wall. Drugs that target ergosterol include the commonly used triazoles (e.g. fluconazole) and formulations of the polyene Amphotericin B, reserved as a last line of defense due to its toxicity. Echinocandins have the advantage of attacking a fungal specific target, 1,3-beta-D-glucan synthase activity which weakens the fungal cell wall. However, drug resistant mutations in FKS1 that prevent echinocandin binding are an increasing problem.
Biofilms are highly structured, multicellular communities of cells embedded in an extracellular matrix and are a key factor in persistent and systemic infections. Although, the development of drug therapies that specifically target biofilms has long been discussed, such drugs have not materialized.
We have generated and characterized a large library genetically tractable yeast strains with different biofilm characteristics. Our genetic and genomic analysis of this collection has identified numerous gene products and at least one small molecule that can module biofilm formation. Many of these potential targets have favorable properties, such as low homology to mammalian proteins and extracellular accessibility. Finally, our lab has developed a unique colony imaging system and automated image analysis software capable of high resolution monitoring of the growth and morphology of a large number (~3,500) of colonies in a single experiment.
Design proteins able to modulate the targets identified in our yeast genetic and genomic analyses and test their effects in disrupting biofilm formation and sensitizing yeast to drugs they are resistant to.