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

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 sm...

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Bibliographic Details
Published in:Nature communications 2014-06, Vol.5 (1), p.4124-4124, Article 4124
Main Authors: Bhowmick, Tuhin, Ghosh, Soumitra, Dixit, Karuna, Ganesan, Varsha, Ramagopal, Udupi A, Dey, Debayan, Sarma, Siddhartha P, Ramakumar, Suryanarayanarao, Nagaraja, Valakunja
Format: Article
Language:English
Subjects:
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
Crystallography, X-Ray
DNA - metabolism
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - metabolism
Gene Expression Regulation, Bacterial - drug effects
Microscopy, Electron
Mycobacterium tuberculosis - genetics
Mycobacterium tuberculosis - metabolism
Mycobacterium tuberculosis - ultrastructure
Protein Structure, Tertiary
Stilbenes - pharmacology
Surface Plasmon Resonance
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Summary: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms5124