Non-quinolone Topoisomerase Inhibitors

Fluoroquinolone antibiotics, such as ciprofloxacin, levofloxacin, and moxifloxacin, have enjoyed enormous success over the past few decades. However, resistance to these compounds is rising and causing significant concern. These drugs target the type II DNA topoisomerases, DNA gyrase, and DNA topoisomerase (topo) IV. A key feature of their success is that they cause enzyme-stabilized double-stranded breaks in DNA, which can readily lead to bacterial cell death. There are, however, many other compounds that target gyrase and topo IV both via the cleavage-complex mode of action and via other modes of inhibition, such as blocking the ATPase activity of these enzymes. The purpose of this chapter is to review our knowledge of these compounds and to discuss the possibility that one or more of these compounds will become clinically-relevant, perhaps by replacing the fluoroquinolones. Compounds covered include well-established agents, such as the aminocoumarins, which predate the quinolones in terms of their discovery, and a variety of more recently-discovered compounds whose clinical potential has yet to be fully explored.