Suryanarayanarao Ramakumar, Bhowmick T., Ghosh S., Dixit K., Ganesan V., Ramagopal UA., Dey D., Sarma SP., Ramakumar S. and Nagaraja V.
Department of Physics, Indian Institute of Science, Bangalore-560012, India
The DNA binding protein HU plays important roles in maintenance of chromosomal architecture and in global regulation of DNA transactions in bacteria. Although HU is essential for growth of Mycobacterium tuberculosis (Mtb) there have been no reported attempts to perturb HU functions with small molecules. We report the crystal structure of the N-terminal domain of HU from Mtb. Applying a novel strategy, we identify a core region within the HU-DNA interface that was targeted using stilbene derivatives. These small molecules specifically inhibit HU-DNA binding, disrupt nucleoid architecture and reduce Mtb growth. Our results indicate that HU is a potential target for the development of therapies against tuberculosis. Work related to the identification of additional pockets and new inhibitors targeting HU is currently underway and the results will be presented.
Keywords: Tuberculosis, HU, core-region, DNA-binding inhibitor, reduced Mtb growth.
Bhowmick T, Ghosh S, Dixit K, Ganesan V, Ramagopal U.A., Dey D, Sarma S.P., Ramakumar S, Nagaraja V. 'Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors'. Nature Communications, June 2014.