7th joint conference "Joint Microbiology & Infection Conference 2024" of the DGHM and VAAM

Abstract: Antifungal drug tolerance and resistance are distinct responses to drugs that inhibit fungal growth. Intrinsic tolerance is a relatively stable property of each isolate characterized by a subpopulation of cells that grow in drug concentrations that inhibit the growth of the overall population. Strains with higher tolerance have a larger subpopulation of cells that can grow in the drug and, on average, those tolerant cells overcome cell cycle arrest earlier than cells with lower tolerance levels. Intrinsic tolerance levels, which differ between C. albicans isolates, are influenced by growth conditions and stresses including temperature, pH, and osmotic stress, with different isolates affected by these conditions and stresses to different degrees. These intrinsic differences between tolerance in different strains are likely a function of the broad diversity of genetic backgrounds, and the many genes involved in the tolerance response. We are testing the hypothesis that antifungal drug tolerance requires a broad range of interdependent physiological processes that operate to different degrees in different isolates across the diversity of the C. albicans species.   
 
Acquired tolerance emerges in newly drug-tolerant cells, usually as a consequence of drug selection. Heterotolerance is a transiently stable type of acquired tolerance usually conferred by the transient genome changes such as aneuploidy or copy number variations. It is thought that the increased level of genes that promote het extra copies of genes that affect drug responses. Relative drug concentration has a dramatic effect on the evolution of survival strategies: Hetero-tolerant colonies arise frequently  
(~1/1000 cells within a single liquid passage) in cultures exposed to supra-MIC drug concentrations, whereas heteroresistance (transiently acquired resistance) appears only after multiple passages at sub-MIC drug concentrations.  Isolates with heterotolerance often carry one of several recurrent aneuploid chromosomes, alone or in combination with other chromosomes.   We are leveraging a large collection (> 1500 isolates) of C. albicans to better understand how genetic, physiological and environmental factors affect the evolutionary trajectories and dynamics with which antifungal drug tolerance and resistance emerge and persist. 

Exploring the diversity of antifungal drug tolerance

Barbarossa Saal

Judith Berman

Plenary Speaker