How transcriptional regulation governs fungal drug resistance

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Antimicrobial resistance (AMR) is a serious clinical and societal problem when using drugs to treat infections in humans and other animals. A common cause of drug resistance is overproduction of 'efflux pumps', which greatly reduce the effectiveness of drugs by pumping them out of cells. Given the importance of efflux pump levels for drug resistance, it is vital to understand how cells regulate production of drug efflux pumps and how overproduction of the pumps can be prohibited.In this project, we will elucidate how the production of drug efflux pumps is controlled in the pathogenic fungus Candida glabrata. C. glabrata is one of the most common causes of fungal infections. C. glabrata infection is associated with high mortality in individuals with compromised immunity, including cancer patients treated with chemotherapy, and transplant recipients who take immunosuppressive drugs. C. glabrata infects humans and also other animals, e.g., birds and cattle. C. glabrata is particularly deadly as a fungal pathogen because it has low susceptibility to azole antifungal agents, and easily develops drug resistance due to overproduction of efflux pumps. Preventing overproduction of these efflux pumps is one good approach to ensure C. glabrata can be killed by existing antifungal drugs. However, overproduction mechanism of the pumps is not understood sufficiently well for us to prevent it.The aim of this project is to reveal mechanisms of overproduction of pumps in order to prevent drug resistance. Utilising our team's expertise in infectious diseases and gene expression, we will dissect the function of a chromatin remodeller complex in regulating pump gene expression. We will also explore pathways to stop drug resistance through using genetic and proteomic approaches and developing an innovative biotechnology for pump removal. This work holds enormous immediate and long-term potential for understanding mechanisms of antifungal resistance of C. glabrata, and for combating antifungal resistance of C. glabrata and potentially other Candida species.