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

Tuhin Bhowmick, Soumitra Ghosh, Karuna Dixit, Varsha Ganesan, Udupi A. Ramagopal, Debayan Dey, Siddhartha P. Sarma, Suryanarayanarao Ramakumar () and Valakunja Nagaraja ()
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Tuhin Bhowmick: Indian Institute of Science
Soumitra Ghosh: Indian Institute of Science
Karuna Dixit: Molecular Biophysics Unit, Indian Institute of Science
Varsha Ganesan: Indian Institute of Science
Udupi A. Ramagopal: Albert Einstein College of Medicine, Jack and Pearl Resnick Campus
Debayan Dey: Indian Institute of Science
Siddhartha P. Sarma: Molecular Biophysics Unit, Indian Institute of Science
Suryanarayanarao Ramakumar: Indian Institute of Science
Valakunja Nagaraja: Indian Institute of Science

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5124

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