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

被引：94

作者：

Bhowmick, Tuhin ^{[1
]}

Ghosh, Soumitra ^{[2
]}

Dixit, Karuna ^{[3
]}

Ganesan, Varsha ^{[2
]}

Ramagopal, Udupi A. ^{[4
,5
]}

Dey, Debayan ^{[1
]}

Sarma, Siddhartha P. ^{[3
]}

Ramakumar, Suryanarayanarao ^{[1
]}

Nagaraja, Valakunja ^{[2
,6
]}

机构：

[1] Indian Inst Sci, Dept Phys, Bangalore 560012, Karnataka, India

[2] Indian Inst Sci, Dept Microbiol & Cell Biol, Bangalore 560012, Karnataka, India

[3] Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India

[4] Albert Einstein Coll Med, Bronx, NY 10461 USA

[5] Poornaprajna Inst Sci Res, Div Biol Sci, Bangalore 562110, Karnataka, India

[6] Jawaharlal Nehru Ctr Adv Sci Res, Bangalore 560064, Karnataka, India

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

关键词：

RESISTANT TUBERCULOSIS; MULTIDRUG-RESISTANT; ACCURATE DOCKING; DRUG DISCOVERY; TRANS-STILBENE; DNA; BINDING; GENES; DATABASE; BIOLOGY;

D O I：

10.1038/ncomms5124

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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