Biophysical Society Thematic Meeting - November 16-20, 2015

Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Speaker Abstracts

Structure-based Discovery of Novel DNA Gyrase B Inhibitors Matjaz Brvar 1 , Andrej Perdih 1 , Tihomir Tomasic 2 , Nace Zidar 2 , Lucija PeterlinMasic 2 , Janez Ilas 2 , Danijel Kikelj 2 , Marko Anderluh 2 , Tom Solmajer 1 . 1 National Institute of Chemistry, Ljubljana, Slovenia, 2 Faculty of Pharmacy University of Ljubljana, Ljubljana, Slovenia. The emergence of bacterial resistance to most of the clinically used antibiotics and the urgent need for the discovery of potent antibacterials with broad spectrum of efficacy and improved safety profile has revived the research in this field [1]. One of the well established targets is the DNA gyrase B[2], a topoisomerase with an ATP-ase activity. In our ongoing effort to identify low molecular weight inhibitors of DNA gyrase B we used structure-based design approach. Starting from the available structural information[3] we identified a series of novel indolinone-2- ones,[4] 2-2-amino-4-(2,4 dihydroxyphenyl)thiazoles,[5] and more recently, 4’-methyl-N2- phenyl-[4,5’-bithiazole]-2,2’-diamine inhibitors of gyrase B with a low micromolar inhibitory activity[6]. These inhibitors were subsequently extensively characterized by various biophysical techniques (differential scanning fluorimetry, surface plasmon resonance and microscale thermophoresis). Further studies resulted in discovery of 4,5-dibromopyrrolamides, indolamides and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazoles[7] as ATP competitive DNA gyrase B inhibitors. Details of a nanomolar inhibitor 4-(4,5-dibromo-pyrrole-2-carboxamido)benzamide binding mode were revealed by high-resolution crystal structure of the complex with E. coli DNA gyrase B.[8] .References[1] E.D. Brown, G. D. Wright, Chem. Rev. 2005, 105, 759.[2] M. Oblak, M. Kotnik, T. Solmajer, Curr. med. chem., 2007, 14, 2033.[3] R.J. Lewis, D.B. Wigley et al., EMBO J. 1996, 15, 1412.[4] M. Oblak, T. Solmajer et al., Bioorg & Med. Chem. Lett. 2005, 15 5207.[5] M. Brvar, T. Solmajer et al., Bioorg. Med. Chem. Lett. 2010, 20, 958.[6] M. Brvar,T. Solmajer et al., J. Med. Chem. 2012, 55, 6413.[7] T. Tomasic, N., T. Solmajer et al., – J. Med.Chem.2015, Articles ASAP .[8] N. Zidar, T. Solmajer et al., - J. Med. Chem.2015, Articles ASAP

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