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
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.