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

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

  • Nat Commun. 2014 Jun 11;5:4124. doi: 10.1038/ncomms5124.
Tuhin Bhowmick 1,  Soumitra Ghosh 2,  Karuna Dixit 3,  Varsha Ganesan 4,  Udupi A Ramagopal 5,  Debayan Dey 6,  Siddhartha P Sarma 3,  Suryanarayanarao Ramakumar 6,  Valakunja Nagaraja 7
Affiliations

Affiliations

  • 1 1] Department of Physics, Indian Institute of Science, Bangalore 560012, India [2].
  • 2 1] Department of Microbiology and Cell biology, Indian Institute of Science, Bangalore 560012, India [2].
  • 3 Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
  • 4 Department of Microbiology and Cell biology, Indian Institute of Science, Bangalore 560012, India.
  • 5 1] Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Ullmann Building, Room 409, Bronx, New York 10461, USA [2] Biological Sciences Division, Poornaprajna Institute of Scientific Research, Bangalore 562110, India.
  • 6 Department of Physics, Indian Institute of Science, Bangalore 560012, India.
  • 7 1] Department of Microbiology and Cell biology, Indian Institute of Science, Bangalore 560012, India [2] Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India.
PMID: 24916461 DOI: 10.1038/ncomms5124
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.

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