Drug responses in Pathogenic Yeasts

Fungal diseases cause > 1.6M deaths annually and mortality from systemic fungal infections remains very high in modern hospitals. Furthermore, the majority of persistent infections are caused by clinically susceptible (not resistant) isolates. Indeed, pathogenic yeasts (much like cancer cells) rapidly find ways to live and grow, despite the presence of inhibitory drug concentrations. Indeed, the majority of problematic (persistent or recurrent) fungal infections are caused by susceptible isolates, despite treatment with drug concentrations above the MIC for the infecting organisms. Clearly, the familiar paradigm of bacterial drug resistance is not entirely applicable to eukaryotic cells, and particularly to eukaryotic pathogens that are treated with fungistatic, rather than fungicidal, drugs. Our motivation is to understand how eukaryotic cells respond rapidly to severe stresses, with the hope of discovering improved antifungal therapy strategies. Tolerance and hetero-resistance are responses in which some of the cells in an isogenic population grow slowly in the presence of supra-MIC drug concentrations. These tolerant subpopulations, together with the selective pressure of drug treatment acting upon them, have the potential to drive the evolution of new mechanisms for survival of the pathogen. One of the rapid routes to stable antifungal drug tolerance is usually via aneuploidy, and its effects on the expression of specific genes. Indeed, aneuploidy is a common, rapid, and transiently stable mechanism by which many different yeast species (including the model yeast S. cerevisiae) respond to many different stress conditions. These and other mechanisms of drug adaptation that are being explored, will be discussed.