Antifungal Tolerance: a subpopulation response to drugs and stress
Drug resistance is a well-studied phenomenon, usually caused by genetic mutations that keep the drug from affecting its cellular target. We have been exploring and defining antifungal tolerance, which is a physiological or epigenetic response to drug stress that affects subpopulations of cells, causing phenotypic heterogeneity: some cells grow (albeit slowly) in the drug, other sister cells do not. We are working to understand the mechanisms that are necessary and sufficient for tolerance and how these mechanisms differ in clinical isolates with very diverse genetic backgrounds. Ultimately, we want to understand the potential for tolerance and for the mechanisms by which tolerance may portend poor clinical outcomes.
Research in this topic is funded by an ERC Synergy grant in conjunction with Dr. Markus Ralser at the Charité University of Medicine, Berlin
CC-BY Ben-Ami R, et al., 2016
Heteroresistance: tiny subpopulations of cells that grow in drug
In both Candida glabrata and Cryptococcus neoformans, a small subpopulation of cells (<<1%) develop resistance to fluconazole and the cells that grow are not stably resistant and thus have been termed “heteroresistant". In C. neoformans, Sionov et al. found that heteroresistance often arises due to an extra copy of a chromosome that carries drug resistance genes. In C. glabrata the mechanism(s) of heteroresistance are not yet known. We are exploring the molecular mechanisms of C. glabrata heteroresistance with the goal of identifying conditions and drugs that can reduce or prevent it. We are also addressing the role of heteroresistance in the appearance of bona fide resistant isolates; in other words, does heteroresistance affect the likelihood that isolates will evolve resistance more rapidly.
Genome dynamics and instability
Changes to chromosome stability, chromosome and/or gene copy number, as well as whole genome ploidy shifts often drive the rapid generation of genetic diversity. We study how these changes affect the phenotype of the organisms and the mechanisms by which chromosome components and chromatin dynamics are executed. We have focused on chromosome components, including origins of replication, centromeres and telomeres, contribute to changes in chromosome stability and in how they affect the regulation of gene expression and the evolution of stress-responsive genes and gene families.
We develop public, open-source tools for working with yeasts, analyzing their genomes and chromosome structure, and measuring and visualizing their responses to drugs and other stresses.