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

Abstract

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.

Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin

“…Interestingly, studies have shown that although quinolone agents target bacterial topoisomerase and gyrase, some quinolones also seem to interact with eukaryotic type II topoisomerase. 39,40 For example, ciprofloxacin has been shown to be a modest enhancer of DNA cleavage mediated by eukaryotic topoisomerase II. 40 Based on this, some quinolones have been tested for their efficacy as anticancer agents.…”

DNA topoisomerase II, genotoxicity, and cancer

“…Quinolones, such as CP-115,953, are the only drugs that show high activity against eukaryotic and prokaryotic type II enzymes [101,[122][123][124][125]. While this last drug class has not yet been exploited to treat cancer, quinolones such as ciprofloxacin and levofloxacin that target bacterial type II topoisomerases are the most active and broad-spectrum oral antibacterials in clinical use [124,126,127].…”

“…While this last drug class has not yet been exploited to treat cancer, quinolones such as ciprofloxacin and levofloxacin that target bacterial type II topoisomerases are the most active and broad-spectrum oral antibacterials in clinical use [124,126,127].…”

“…For example, etoposide is a non-intercalative compound that displays weak, if any, interaction with DNA in the absence of topoisomerase II [81,128]. Similarly, genistein and quinolones are also non-intercalative [101,[123][124][125]129]. In contrast, amsacrine, doxorubicin, and mitoxantrone are all intercalative in nature, and the latter two compounds bind DNA with very high affinities [130][131][132].…”

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies

“…The antibacterial fluoroquinolones have been found to be one of the fastest growing groups of drugs in recent years [5][6][7][8] . Quinolones are known for their antibacterial and antitumor activities through alteration of the normal functions of bacterial gyrase, and are found to be a topoisomerase II inhibitor in humans [9][10][11][12][13][14][15][16][17][18] . Ciprofloxacin (Figure 1), a commonly used broadspectrum fluoroquinolone antibiotic, has shown anticancer activity in several cancer cell lines 19,20 .…”