Structure-based discovery of substituted 4,5'-bithiazoles as novel DNA gyrase inhibitors.
Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4'-methyl-N(2)-phenyl-[4,5'-bithiazole]-2,2'-diamine inhibitors of gyrase B with a low micromolar inhibitory activity by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance, and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallography, confirming our initial in silico binding model. Furthermore, the high resolution of the complex structure allowed for the placement of the Gly97-Ser108 flexible loop, thus revealing its role in binding of this class of compounds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable information for further optimization of this novel class of DNA gyrase B inhibitors.
National Institute of Chemistry, Laboratory for Biocomputing and Bioinformatics, 1001 Ljubljana, Slovenia.
Matjaž
M
Brvar
Andrej
A
Perdih
Miha
M
Renko
Gregor
G
Anderluh
Dušan
D
Turk
Tom
T
Solmajer
D000255:Adenosine Triphosphate / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D009675:Novobiocin / Q000031:analogs & derivatives / Q000378:metabolism; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D009675:Novobiocin; C006260:clorobiocin; D000255:Adenosine Triphosphate; D027081:DNA Gyrase