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Understanding Molecular Mechanisms Using Structural Biology Approaches

My laboratory elucidates molecular mechanisms underlying key pathways from human pathogens like Mycobacterium tuberculosis using X-ray crystallography, biochemical/biophysical studies, NMR, and rational structure-based computational analyses. The results are subsequently translated using rational structure-based computational approaches to develop inhibitors with therapeutic potential and new mode(s) of action. Development of new anti-TB therapeutics presents a huge challenge primarily because of the pathogen's ability to evade and persist in the human host for years/decades in a latent/persistent state. Long treatment durations of 6-18 months involving a cocktail of drugs are administered to the patient. Non-compliance has primarily led to the development of Multi- drug resistant (MDR), Extremely drug-resistant (XDR), and even Totally drug resistant (TDR) TB strains. Some of the lab's ongoing work is centered around DNA Base Excision Repair (BER), EsX/TypeVII secretion systems, Feast/Famine regulation, Factors implicated in TB persistence, etc. Since the current crop of anti-TB drugs are not known to primarily act on these pathways, development of new compounds that interfere with these factors represents a strategy to overcome present drug-resistance issues.

Selected Recent Publications

image01Abhishek Dey, Sonal Shree, Sarvesh Kumar Pandey, Rama Pati Tripathi & Ravishankar Ramachandran (2016) Crystal Structure of Mycobacterium tuberculosis H37Rv AldR (rv2779c), a regulator of the ald gene: DNA-binding, and identification of small-molecule inhibitors. J. Biol.Chem. (in press, 2016)
image01Sonal Shree, Abhishek Kumar Singh, Richa Saxena, Harish Kumar, Aparna Agarwal, Vijay Kumar Sharma, Kanchan Srivastava, Kishore Kumar Srivastava, Sabyasachi Sanyal and Ravishankar Ramachandran (2016) The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins and is inhibited by Clofazimine. Cell. Mol. Life Sci. (in press, 2016)
image01Tripathi SM, Agarwal A & Ravishankar Ramachandran (2015) Mutational analysis of Mycobacterium tuberculosis lysine ɛ-aminotransferase and inhibitor co-crystal structures, reveals distinct binding modes. Biochem Biophys Res Commun 463, 154-160.
image01Taran Khanam, Niyati Rai & Ravishankar Ramachandran (2015) Mycobacterium tuberculosis class II apurinic/apyrimidinic-endonuclease/3'-5' exonuclease III exhibits DNA regulated modes of interaction with the sliding DNA β-clamp Mol. Microbiol. 98, 46-68.
image01Nisha Yadav, Taran Khanam, Ankita Shukla, Niyati Rai, Kanchan Hajela & Ravishankar Ramachandran (2015) Tricyclic dihydrobenzoxazepine and Tetracyclic indole derivatives can specifically target bacterial DNA ligases and can distinguish between the human DNA Ligase I. Organic & Biomolecular Chemistry, 13, 5475-5487.