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Title: Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors
Authors: Bhowmick, Tuhin
Ghosh, Soumitra
Dixit, Karuna
Ganesan, Varsha
Ramagopal, Udupi A.
Dey, Debayan
Sarma, Siddhartha P.
Ramakumar, Suryanarayanarao
Nagaraja, V.
Keywords: Resistant Tuberculosis
Accurate Docking
Drug Discovery
Issue Date: 2014
Publisher: Nature Publishing Group
Citation: Bhowmick, T; Ghosh, S; Dixit, K; Ganesan, V; Ramagopal, UA; Dey, D; Sarma, SP; Ramakumar, S; Nagaraja, V, Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors. Nature Communications 2014, 5, 4124
Nature Communications
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.
Description: Restricted Access
ISSN: 2041-1723
Appears in Collections:Research Articles (Nagaraja, V.)

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