A Chemical Microbiology Approach to Study Efflux Mediated Resistance and Develop New Therapeutics Against Drug-resistant Candida spp

A number of fungal pathogens have become major agents of infection in patients with suppressed immunity, often due to factors such as age or cancer therapy. These include yeast species like Candida albicans and Candida auris—the latter being a recently emerged, drug-resistant species associated with significant mortality in infected patients. Candida auris is frequently resistant to more than one class of currently used antifungal drugs. This multidrug resistance (MDR) characteristic of C. auris is also increasingly observed in other Candida species. The emergence of MDR fungal pathogens is particularly concerning due to the relatively limited range of antifungal drugs available to clinicians. It is, therefore, an urgent priority to develop new and effective treatments for MDR Candida spp. The project explores one of the key mechanisms that underpins the multidrug resistant properties of C. auris and other Candida spp. Many of these species have an array of drug efflux pumps, complex molecular machines which are able to transport the antifungal drug out of the cell and stop it reaching levels where it can either kill the fungus or stop it growing. These pumps often work in concert with other resistance mechanisms to achieve very high levels of stable resistance to the drugs used in the clinic - adversely affecting treatment outcomes. Understanding and overcoming the action of these efflux pump systems is essential if we are ever to explain why current drugs are not effective against new clinical isolates, and to guide the development of new analogues of existing drugs which will not be transported out of the cell. This is equally important in the development of new antifungals that might also be susceptible to efflux through these same pumps. Previous work on preventing efflux in azole antifungals have generated compounds that kill MDR Candida spp. including strains with target mutations and high level of expression of efflux pumps. The proposed project will explore the use of these efflux-resistant compounds as tools to define the function of different types of efflux pumps, identifying which are most important in resistance to clinical drugs, and understanding how they interact with other resistance mechanisms within the cell. By combining these chemical tools with state-of-the-art methods for genome modification —such as blocking the production of specific efflux pumps or modifying their activity—we will establish how these novel chemical tools interact with and block the individual efflux pumps they target. Subsequently, we will evaluate how Candida species respond to these new efflux-resistant azole compounds in a complex biological system using mouse models. This approach will help generate a framework to better understand the targeting of drug efflux to support the future development of more effective efflux-resistant drugs.