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Novel insights to antibiotic targets

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Enzymes called topoisomerases “unwind” DNA and are required for processes including replication.

Although the bacterial topoisomerases gyrase and topoisomerase IV are critical for cell function and are targets for quinolone antibacterials (such as Cipro), little is known about how these enzymes remove positive supercoils on overwound DNA.

Neil Osheroff, Ph.D., and colleagues report in Nucleic Acids Research that gyrase removes positive supercoils rapidly and uses a DNA wrapping mechanism to unwind DNA.

They found that gyrase maintains lower levels of cleavage complexes – the enzyme-DNA interaction that is the target of quinolones – on positively versus negatively supercoiled DNA. In contrast, topoisomerase IV removed positive supercoils more slowly than gyrase and generated similar levels of cleavage complexes on both types of supercoiled DNA.

The findings provide novel insights into the activities of these critical enzymes and suggest that their unique abilities to recognize DNA geometry make them well suited to their roles. The findings may have implications for improving the efficacy of quinolone antibacterials.

This research was supported by a U.S. Veterans Administration Merit Review Award (I01 Bx002198) and by grants from the National Institutes of Health (GM033944, AI081775, HL001056) and National Science Foundation (DGE-0909667).

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