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Genome dynamics of the human fungal pathogen Candida albicans

Final Report Summary - GENOMEDYNAMICS (Genome dynamics of the human fungal pathogen Candida albicans)

Fungal infections are becoming more prevalent across the globe and resistance to the scant number of available antifungal drugs is emerging as a significant obstacle to effective antifungal therapies. Antibacterial resistance and multiple drug resistance is well studied and there are many different types of available antibacterial drugs. By contrast, anti-fungal drug resistance is only beginning to be understood, in part because genome dynamics, the organization of DNA within a cell and its transmission to other cells, is fundamentally different in bacteria than in fungi. Specifically, fungi are more similar to animals and plants than to bacteria and most drugs that inhibit fungal growth also have undesirable effects on humans. Thus, an important challenge is to design effective therapeutic strategies that prevent and/or treat fungal infections. Furthermore, such strategies need to avoid the rapid evolution of drug resistance that we found can often be due to changes in the number and/or structure of chromosomes within a pathogenic fungus.

A classic example is Candida albicans, a yeast pathogen that usually lives peacefully in the gut of the majority of humans. While usually in harmless coexistence with other microbial cells, C. albicans can become a pathogen, and as such is the most frequently isolated fungal pathogen in clinical microbiology labs. The most serious candidal infections occur if the organism enters the bloodstream, where it can cause mortality of up to 40% in US hospitals. We found that the rapid acquisition of the ability to survive and grow in the presence of the drug, albeit slowly, is an important and understudied strategy used by the pathogen. This study focuses on the mechanisms by which Candida rapidly develops antifungal drug responses including survival, tolerance/perseverance and heteroresistance in the presence of high drug concentrations.

The Berman lab first developed a series of important tools for studying not only drug resistance but the ability to grow slowly at high drug concentration. Many of these tools leveraged image analysis approaches to monitor the growth of subpopulations of yeasts. We can now quantitate the average growth and subpopulation growth at the population level, at the level of small colonies and at the level of single cells. We developed assays to carefully measure drug perseverance (survival and slow growth of a large subpopulation of cells in high drug concentrations) as well as resistance (growth of all cells at high drug concentrations) in a one-step, common clinical assay. They also streamlined assays of hetero-resistance, the ability of small subpopulations of cells to survive and grow in high drug concentrations. These dynamic studies are revealing new insights into the process by which cells become able to survive and grow in the presence of inhibitory drugs. In addition, they adapted and developed a novel approach to generate very large collections of mutant isolates of a given strain and to then ask which genes in that isolate are important for drug responses.

Using these tools together with established molecular, cellular and biochemical approaches, the Berman lab is also delving into the different molecular and behavioral trajectories used by C. albicans to survive in the presence of antifungal drug concentrations that normally inhibit growth of the organism. This work has the potential to shift the current paradigms of drug responses and to identify new routes to the development of antifungal therapies.