Chapter 19 Recent Advances in the Inhibition of Bacterial Type II Topoisomerases

Publisher Summary Bacterial topoisomerases are divided into two main groups: (1) Type I, which involves DNA single-strand processing and (2) Type II, which processes double-stranded DNA. To date, no advanced inhibitors of bacterial Type I topoisomerases have been reported. In contrast, the useful inhibitors of Type II topoisomerases are abundant. The two principal subclasses of bacterial Type II topoisomerase are DNA gyrase and topoisomerase IV. Tetrameric topoisomerase IV is closely related to DNA gyrase and consists of two subunits of ParC and two subunits of ParE, with ParE containing the ATP-binding pocket. Novobiocin and cyclothialidine inhibit DNA gyrase and topoisomerase IV by binding to the ATP sites in GyrB and ParE, respectively, while the quinolone class inhibits these enzymes by binding to a site in GyrA and ParC near the intersection of the subunits and the associated DNA strand. However, outside the ATP sites, details of the way inhibitors bind are only emerging. This chapter broadly organizes the small-molecule inhibitors of bacterial Type II topoisomerase into those that bind at the ATP sites and those that bind at other sites within the enzyme tetramers.