Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde

Citation
Ve. Anderson et N. Osheroff, Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde, CUR PHARM D, 7(5), 2001, pp. 337-353
Citations number
149
Categorie Soggetti
Pharmacology & Toxicology
Journal title
CURRENT PHARMACEUTICAL DESIGN
ISSN journal
13816128 → ACNP
Volume
7
Issue
5
Year of publication
2001
Pages
337 - 353
Database
ISI
SICI code
1381-6128(200103)7:5<337:TITATF>2.0.ZU;2-3
Abstract
Quinolones are a very important family of antibacterial agents that are wid ely prescribed for the treatment of infections in humans. Although the foun ding members of this drug class had little clinical impact, successive gene rations include the most active and broad spectrum oral antibacterials curr ently 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 topoisomera se IV, and induce them to kill cells by generating high levels of double-st randed DNA breaks. A second unique aspect of quinolones is their differenti al ability to target these two enzymes in different bacteria. Depending upo n the bacterial species and quinolone employed, either DNA gyrase or topois omerase IV serves as the primary cytotoxic target of drug action. While thi s unusual feature initially stymied development of quinolones with high act ivity against Gram-positive bacteria, it ultimately opened new vistas for t he clinical use of this drug class. In addition to the antibacterial quinol ones, specific members of this drug family display high activity against eu karyotic 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 ex amine drug mechanism across divergent species. Because of the clinical impo rtance of quinolones, this review will discuss the mechanistic basis for dr ug efficacy and interactions between these compounds and their topoisomeras e targets.