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Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Speaker Abstracts
41
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