Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors

Bhowmick, Tuhin and Ghosh, Soumitra and Dixit, Karuna and Ganesan, Varsha and Ramagopal, Udupi A and Dey, Debayan and Sarma, Siddhartha P and Ramakumar, Suryanarayanarao and Nagaraja, Valakunja (2014) Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors. In: NATURE COMMUNICATIONS, 5 .

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Abstract

The nucleoid-associated protein HU plays an important role in maintenance of chromosomal architecture and in global regulation of DNA transactions in bacteria. Although HU is essential for growth in Mycobacterium tuberculosis (Mtb), there have been no reported attempts to perturb HU function with small molecules. Here we report the crystal structure of the N-terminal domain of HU from Mtb. We identify a core region within the HU-DNA interface that can be targeted using stilbene derivatives. These small molecules specifically inhibit HU-DNA binding, disrupt nucleoid architecture and reduce Mtb growth. The stilbene inhibitors induce gene expression changes in Mtb that resemble those induced by HU deficiency. Our results indicate that HU is a potential target for the development of therapies against tuberculosis.

Item Type:	Journal Article
Publication:	NATURE COMMUNICATIONS
Publisher:	NATURE PUBLISHING GROUP
Additional Information:	Copy right for this article belongs to the NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit Division of Biological Sciences > Microbiology & Cell Biology Division of Physical & Mathematical Sciences > Physics
Date Deposited:	13 Aug 2014 11:59
Last Modified:	13 Aug 2014 11:59
URI:	http://eprints.iisc.ac.in/id/eprint/49643

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