Community Research and Development Information Service - CORDIS


RAPLODAPT Report Summary

Project ID: 340087
Funded under: FP7-IDEAS-ERC
Country: Israel

Mid-Term Report Summary - RAPLODAPT (Ploidy change as a rapid mechanism of adaptation)

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 is often transmitted and amplified on plasmids, small circles of DNA that can be amplified to high copy in a single cell and that spread between individual bacteria and even across bacterial species. 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 eukaryotes, with cell components like those of plants and animals. Indeed, one of the challenges of designing new classes of antifungal drugs is that there are few drugable targets that are sufficiently different between pathogenic fungi and their hosts.

Candida albicans, a yeast pathogen that usually lives peacefully in the majority of humans, can also become a pathogen. Indeed, C. albicans is the most commonly isolated fungal pathogen in clinical microbiology labs. The yeast exploits opportunities, such as suppressed immunity that fails to keep it in check, to spread in the gut, the female reproductive tract. More serious infections arise if it enters the bloodstream, where it causes mortality of up to 40% in Western hospitals that have antifungal drugs available. Part of the failure to treat fungal infections is the ability of C. albicans to rapidly develop antifungal drug tolerance, persistence and/or resistance. This study focuses on the mechanisms by which yeasts rapidly develop antifungal drug responses.

Before embarking on new studies of rapid adaptation to antifungal drugs, the Berman lab developed a series of important tools for studying the phenomenon at many different levels: from populations to thousands of individual cells over a time course and under different drugs and stresses. They developed a method to carefully measure drug tolerance as well as resistance in a one-step, common clinical assay; they also developed a series of tools to follow individual cells, small groups of cells and clonal populations of cells over time. 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 that C. albicans uses to survive in antifungal drugs. This work has the potential to shift the current paradigms of drug tolerance and persistence and to identify new routes to the development of antifungal therapies.

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