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Type II Topoisomerases as Targets for Quinolone Antibacterials Turning Dr. Jekyll into Mr. Hyde

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Quinolones are a very important family of antibacterial agents that are widely prescribed for the treatment of infections in humans. Although the founding members of this drug class had little clinical impact, successive generations include the most active and broad spectrum oral antibacterials currently in use. In contrast to most other anti-infective drugs, quinolones do not kill bacteria by inhibiting a critical cellular process. Rather, they corrupt the activities of two essential enzymes, DNA gyrase and topoisomerase IV, and induce them to kill cells by generating high levels of double-stranded DNA breaks. A second unique aspect of quinolones is their differential ability to target these two enzymes in different bacteria. Depending upon the bacterial species and quinolone employed, either DNA gyrase or topoisomerase IV serves as the primary cytotoxic target of drug action. While this unusual feature initially stymied development of quinolones with high activity against Gram-positive bacteria, it ultimately opened new vistas for the clinical use of this drug class. In addition to the antibacterial quinolones, specific members of this drug family display high activity against eukaryotic type II topoisomerases, as well as cultured mammalian cells and in vivo tumor models. These antineoplastic quinolones represent a potentially important source of new anticancer agents and provide an opportunity to examine drug mechanism across divergent species. Because of the clinical importance of quinolones, this review will discuss the mechanistic basis for drug efficacy and interactions between these compounds and their topoisomerase targets.
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Keywords: Amscrine; Antineoplastic Quinolones; E. Coli DNA Gyrase; Etoposide; Eukaryotic Topoisomerase II; Human Topoisomerase; Nalidixic acid; Oxolinic acid; Quinolone Antibacterials; Type II Topoisomerases

Document Type: Review Article

Publication date: March 1, 2001

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  • Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.

    Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.
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