Structural highlights
Function[GYRB_ECOLI] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.[1] [2] [3] Publication Abstract from PubMedBacterial DNA gyrase and topoisomerase IV control the topological state of DNA during replication and are validated targets for antibacterial drug discovery. Starting from our recently reported 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-based DNA gyrase B inhibitors, we replaced their central core with benzothiazole-2,6-diamine scaffold and interchanged substituents in positions 2 and 6. This resulted in equipotent nanomolar inhibitors of DNA gyrase from Escherichia coli displaying improved inhibition of Staphylococcus aureus DNA gyrase and topoisomerase IV from both bacteria. Compound 27 was the most balanced inhibitor of DNA gyrase and topoisomerase IV both from E. coli and S. aureus. The crystal structure of the 2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzothiazol-6-yl)amino)-2-oxoacetic acid (24) in complex with E. coli DNA gyrase B revealed the binding mode of the inhibitor in the ATP-binding pocket. Only some compounds possessed weak antibacterial activity against Gram-positive bacteria. These results provide a basis for structure-based optimization towards dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity. Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors.,Gjorgjieva M, Tomasic T, Barancokova M, Katsamakas S, Ilas J, Tammela P, Peterlin Masic L, Kikelj D J Med Chem. 2016 Aug 19. PMID:27541007[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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This page was last modified 14:00, 10 September 2016.