title: Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase.
abstract: Tuberculosis is a serious infectious disease caused by human pathogen bacteria Mycobacterium tuberculosis. Bacterial drug resistance is a very significant medical problem nowadays and development of novel antibiotics with different mechanisms of action is an important goal of modern medical science. Leucyl-tRNA synthetase (LeuRS) has been recently clinically validated as antimicrobial target. Here we report the discovery of small-molecule inhibitors of M. tuberculosis LeuRS. Using receptor-based virtual screening we have identified six inhibitors of M. tuberculosis LeuRS from two different chemical classes. The most active compound 4-{[4-(4-Bromo-phenyl)-thiazol-2-yl]hydrazonomethyl}-2-methoxy-6-nitro-phenol (1) inhibits LeuRS with IC50 of 6μM. A series of derivatives has been synthesized and evaluated in vitro toward M. tuberculosis LeuRS. It was revealed that the most active compound 2,6-Dibromo-4-{[4-(4-nitro-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenol inhibits LeuRS with IC50 of 2.27μM. All active compounds were tested for antimicrobial effect against M. tuberculosis H37Rv. The compound 1 seems to have the best cell permeability and inhibits growth of pathogenic bacteria with IC50=10.01μM and IC90=13.53μM.
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Olga I
authors.initials: OI
authors.lastname: Gudzera
authors.affiliation: OTAVA Ltd, 400 Applewood Crescent, Unit 100, Vaughan, Ontario L4K0C3, Canada.
authors.forename: Andriy G
authors.initials: AG
authors.lastname: Golub
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Volodymyr G
authors.initials: VG
authors.lastname: Bdzhola
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Galyna P
authors.initials: GP
authors.lastname: Volynets
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Sergiy S
authors.initials: SS
authors.lastname: Lukashov
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Oksana P
authors.initials: OP
authors.lastname: Kovalenko
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Kriklivyi
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Anna D
authors.initials: AD
authors.lastname: Yaremchuk
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Sergiy A
authors.initials: SA
authors.lastname: Starosyla
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine. Electronic address: sergiy@yarmoluk.org.ua.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Yarmoluk
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: Michail A
authors.initials: MA
authors.lastname: Tukalo
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007935:Leucine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology*; D009596:Nitrophenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D007935:Leucine-tRNA Ligase
keywords: Aminoacylation assay; Inhibitor; Leucyl-tRNA synthetase; Mycobacterium tuberculosis; Virtual screening