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Title: A journey of 25 years with a multi drug transporter: a lot more to discover.
Speaker: Prof Rajendra Prasad, Amity Institute of Biotechnology, Amity Institute of Integrative Science and Health, Amity University Gurgaon, Haryana, India
Date: 22nd March, 2023 (Wednesday), 5:30 PM – 6.30 PM C V Raman Hall, IISER Tirupati Transit Campus
Abstract: The phenomenon of Candida cells acquiring multidrug resistance (MDR) is common. This, however, hampers their successful chemotherapy. Candida infections are largely contained by the use of azole drug fluconazole (FLU), other topical azoles and polyene drugs. The excessive use of FLU has however, resulted in the emergence of azole‐resistant (AR) strains of Candida. Reduced intracellular accumulation of drugs (due to rapid efflux) is one of the most prominent mechanisms of resistance in Candida cells. Accordingly, clinical AR isolates of C. albicans display transcriptional activation of genes, encoding ATP Binding Cassette (ABC) multidrug transporter proteins Cdr1p or Cdr2p or Major Facilitator Super family (MFS) efflux pump protein Mdr1p. To date, the research on structural and functional characterizations of drug efflux pump proteins of C. albicans is very limited. Of the two major MDR pump proteins, i.e. Cdr1 and Mdr1 proteins, there have been extensive mutational studies done by us with Cdr1 protein and thus, reasonable amount of information exists to suggest the nature of drug binding and transport. As a result of our efforts, we have begun to understand the basis of promiscuity of these proteins, nature of drug binding cavity, critical amino acidsof ATP catalysis and drug efflux (particularly in case of Cdr1p), however, it still requires more efforts to elucidate the molecular basis of the functioning of these proteins.
The sudden emergence of Candida auris and its pan resistant behavior has compelled researchers to look for unconventional strategies which might explain its display of very high resistance towards common antifungals. We recently experimentally evolved drug- susceptible isolates of C.auris for multiple generations in the presence of the antifungal compound FLU. The changes in the karyotype, DNA sequence, and gene expression profiles in adapted drug-resistant isolates is providing newer insights into the strategies that help adapt C.auris cells to higher resistance. These studies are providing clues which are also relevant to clinical settings.
