title: Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors.
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.
authors.affiliation: 1] Department of Physics, Indian Institute of Science, Bangalore 560012, India [2].
authors.forename: Tuhin
authors.initials: T
authors.lastname: Bhowmick
authors.affiliation: 1] Department of Microbiology and Cell biology, Indian Institute of Science, Bangalore 560012, India [2].
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Karuna
authors.initials: K
authors.lastname: Dixit
authors.affiliation: Department of Microbiology and Cell biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Varsha
authors.initials: V
authors.lastname: Ganesan
authors.affiliation: 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.
authors.forename: Udupi A
authors.initials: UA
authors.lastname: Ramagopal
authors.affiliation: Department of Physics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Debayan
authors.initials: D
authors.lastname: Dey
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Siddhartha P
authors.initials: SP
authors.lastname: Sarma
authors.affiliation: Department of Physics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Suryanarayanarao
authors.initials: S
authors.lastname: Ramakumar
authors.affiliation: 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.
authors.forename: Valakunja
authors.initials: V
authors.lastname: Nagaraja
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D008854:Microscopy, Electron; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D013267:Stilbenes / Q000494:pharmacology*; D020349:Surface Plasmon Resonance
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D013267:Stilbenes; C040330:histone-like protein HU, bacteria; D004247:DNA