Fig. 1: Overview of antifungal drug responses.

Antifungal drug resistance (left side) is detected as elevated MIC due to direct effects on drug (orange circle) or drug target (blue star), via reduced binding affinity of the target for the drug, increased levels of the target that dilute the drug effect, or by reducing the intracellular drug concentration via drug efflux or blocked drug uptake. Antifungal drug tolerance (right side) is a physiological response to drug stress involving pathways that buffer the stress, such that some cells are able to grow, albeit slowly, in the presence of drug concentrations that are inhibitory to other cells in the population. This involves physiological shifts in: the cell wall or membrane integrity pathways (including pathways regulated by Hsp90, calcineurin, and the Crz1 transcription factor, and pathways affecting membrane lipid composition); protein translation machinery including the TOR pathway; and modifications of mitochondrial function. Loss of mitochondrial DNA in tolerant species (e.g., C. glabrata and Saccharomyces cerevisiae), also leads to high drug efflux via Pdr1 and drug resistance, but cellular fitness is highly compromised in these ‘petite’ isolates, which are therefore not thought to be clinically relevant. Heteroresistance (across top) is a semi-stable mechanism, often due to whole chromosome aneuploidy, that can confer either resistance (increased MIC), via increased expression of a target or of efflux pumps, or tolerance (susceptible MIC but increased growth in drug) via altered stress response pathways. Biofilms (bottom) are a sessile physiological state that grows slowly and exhibits drug resistance and/or tolerance due to multiple mechanisms, including sequestration of the drug by large amounts of extracellular matrix. Aneuploidy, gene amplification, copy number variation and loss of heterozygosity (LOH) can confer resistance or tolerance, depending on the specific genes and combinations of genes that are involved.