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

Author

Listed:
  • 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
    Poornaprajna Institute of Scientific Research)

  • 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
    Jawaharlal Nehru Centre for Advanced Scientific Research)

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.

Suggested Citation

  • Tuhin Bhowmick & Soumitra Ghosh & Karuna Dixit & Varsha Ganesan & Udupi A. Ramagopal & Debayan Dey & Siddhartha P. Sarma & Suryanarayanarao Ramakumar & Valakunja Nagaraja, 2014. "Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors," Nature Communications, Nature, vol. 5(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5124
    DOI: 10.1038/ncomms5124
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    Cited by:

    1. Prakruti R. Singh & Venkatareddy Dadireddy & Shubha Udupa & Shashwath Malli Kalladi & Somnath Shee & Sanjeev Khosla & Raju S. Rajmani & Amit Singh & Suryanarayanarao Ramakumar & Valakunja Nagaraja, 2023. "The Mycobacterium tuberculosis methyltransferase Rv2067c manipulates host epigenetic programming to promote its own survival," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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