Linus. L. Shen*, S. Ken Tanaka and Daniel. T.W. Chu Pages 169 - 176 ( 8 )
DNA gyrase and topoisomerase IV, the bacterial type II DNA topoisomerases, are known to be the targets of fluoroquinolones. The fluoroquinolones have rapid bactericidal action derived from their dual actions to inhibit the catalytic activity of the essential enzymes and to form a stable enzyme-DNA cleavable complex. These actions lead to a quick arrest of DNA replication, inhibition of DNA segregation and induction of irreversible DNA damage. These inhibitors have a relatively simple chemical structure, but are extremely potent with antibacterial activity reaching to a few nanograms per milliliter. The high potency and specificity of the inhibitor are believed to be achieved, using DNA gyrase as a model, by their unique capability to bind cooperatively to a partially denatured DNA pocket created by the target enzyme during the strand breaking-passing steps of the catalysis. The future of the clinical use of quinolones is shadowed by the recent development of resistance which primarily results from mutations in the structural genes of the target enzymes. Therefore, one of the current efforts in this area of research is to develop means to overcome the drug resistance. Using a filter-binding assay, we found that ABT-719, a recently discovered compound in the new 2-pyridone family, has unique activity toward resistant E. coli DNA gyrase and topoisomerase IV. Differe11tial activity analysis also demonstrate that the 2-pyridone is more potent against DNA gyrase than topoisomerase IV in terms of their DNA breakage activity in vitro. This is consistent with the genetic analysis results obtained with E. coli that the primary target of these drugs is DNA gyrase but not topoisomerase IV. Using the 'conformation switch model', we hypothesize that this class of compound may have unique capability to fit the mutated binding site which consists of both DNA and the enzyme.