Functional Insight Into The Promiscuous Role Of Multidrug Transporters Of Candida Albicans | 40644
Journal of Biotechnology & Biomaterials
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Among the 28 putative ABC transporters and 95 putative MFS transporters identified in the C. albicans genome, only
CaCdr1p and CaCdr2p and the MFS transporter CaMdr1p are major determinants of azole resistance and variety of
structurally unrelated compounds such as lipids and steroids. The architecture of the drug-binding sites and promiscuity
towards substrates is essential to understand the drug-protein interaction and provide a platform for rational design of
modulators/inhibitors. Also the reversal of azole resistance is considered an attractive strategy to desensitize the multidrug
resistant clinical isolates of C. albicans. Therefore, we have explored the poly-specific nature of the Cdr1 protein by screening its
in-house mutant library with varied range of chemically related and unrelated compounds. Based on the biochemical mapping
of essential residues, we established the substrate specificity of Cdr1p to be independent of size, charge and hydrophobicity.
Our study also established the molecular basis of interaction of an immunosuppressant FK520 with Cdr1p and deduced the
role of critical amino acids of the transporter protein, which if replaced with alanine, not only abrogated FK520-dependent
competitive inhibition of drug efflux but simultaneously decreased susceptibility to azoles. Another class of compounds,
macrocyclic diterpenes derived from Euphorbia species, reported as strong modulators of the transport activity of the human
P-glycoprotein where found to inhibit drug-efflux activity and render fluconazole sensitization to CaCdr1p and CaMdr1p
which may constitute valuable leads for developing effective modulators of C. albicans multidrug transporters.
Shweta Nim is currently pursuing her PhD with title “Understanding the Promiscuity of Multidrug Transporter of Candida albicans” under the guidance of Professor Rajendra Prasad from Jawaharlal Nehru University, India. In her two years of PhD, she has published her part of work in “Fems Yeast Research” in 2014, which has been acknowledged as the “Editor’s choice Paper of the month” and other communicated in Journal of Phytomedicine on June 4, 2015. She has completed her Master of Science and Master of Philosophy in Life Sciences from Jawaharlal Nehru University, India.