Exploring Antifungal Drugs Produced by Brewer's Yeasts
Additional Funding Sources
The project described was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant No. P20GM103408. The project described was supported by a student grant from the UI Office of Undergraduate Research.
Abstract
Combatting the spread of drug-resistant microbes requires new antifungal compounds with novel mechanisms of inhibition. We are investigating natural, proteinaceous toxins that are encoded by double stranded RNA satellites found within Saccharomyces cerevisiae. Commonly known as killer yeasts, toxin-producing strains of S. cerevisiae have been found to inhibit the growth of many fungal pathogens. By testing over 9,000 interactions between killer yeasts and pathogens we determined that Candida glabrata is broadly susceptible to killer toxins, while other Candida species showed little to no susceptibility. Of the 90 killer strains of S. cerevisiae tested against C. glabrata several were capable of inhibiting all drug-resistant, clinical isolates available from the CDC/FDA. In our evaluation of these toxins as potential antifungal therapeutics we confirmed their inhibitory capability against C. glabrata under several key physiological conditions. Then, to proactively investigate the inevitable resistance to these toxins that would arise in a clinical setting we went on to generate toxin resistant mutants of C. glabrata in order to study natural toxin resistance mechanisms. We completed characterization of these mutants based on cell morphology, colony morphology, growth rate, and cross resistance to several classes of killer toxins. These tests gave us a preliminary understanding of the fitness cost of killer toxin resistance. Based on the results of these tests and prior knowledge about "killer" yeasts, we believe that these toxins show strong potential as antifungal therapeutic precursors.
Exploring Antifungal Drugs Produced by Brewer's Yeasts
Combatting the spread of drug-resistant microbes requires new antifungal compounds with novel mechanisms of inhibition. We are investigating natural, proteinaceous toxins that are encoded by double stranded RNA satellites found within Saccharomyces cerevisiae. Commonly known as killer yeasts, toxin-producing strains of S. cerevisiae have been found to inhibit the growth of many fungal pathogens. By testing over 9,000 interactions between killer yeasts and pathogens we determined that Candida glabrata is broadly susceptible to killer toxins, while other Candida species showed little to no susceptibility. Of the 90 killer strains of S. cerevisiae tested against C. glabrata several were capable of inhibiting all drug-resistant, clinical isolates available from the CDC/FDA. In our evaluation of these toxins as potential antifungal therapeutics we confirmed their inhibitory capability against C. glabrata under several key physiological conditions. Then, to proactively investigate the inevitable resistance to these toxins that would arise in a clinical setting we went on to generate toxin resistant mutants of C. glabrata in order to study natural toxin resistance mechanisms. We completed characterization of these mutants based on cell morphology, colony morphology, growth rate, and cross resistance to several classes of killer toxins. These tests gave us a preliminary understanding of the fitness cost of killer toxin resistance. Based on the results of these tests and prior knowledge about "killer" yeasts, we believe that these toxins show strong potential as antifungal therapeutic precursors.