Activity of Quinolone CP-115,955 Against Bacterial and Human Type II Topoisomerases Is Mediated by Different Interactions

Abstract

CP-115,955 is a quinolone with a 4-hydroxyphenyl at C7 that displays high activity against both bacterial and human type II topoisomerases. To determine the basis for quinolone cross-reactivity between bacterial and human enzymes, the activity of CP-115,955 and a series of related quinolones and quinazolinediones against Bacillus anthracis topoisomerase IV and human topoisomerase IIα was analyzed. Results indicate that the activity of CP-115,955 against the bacterial and human enzymes is mediated by different interactions. Based on the decreased activity of quinazolinediones against wild-type and resistant mutant topoisomerase IV and the low activity of quinolones against resistant mutant enzymes, it appears that the primary interaction of CP-115,955 with the bacterial system is mediated through the C3/C4 keto acid and the water-metal ion bridge. In contrast, the drug interacts with the human enzyme primarily through the C7 4-hydroxyphenyl ring and has no requirement for a substituent at C8 in order to attain high activity. Despite the fact that the human type II enzyme is unable to utilize the water-metal ion bridge, quinolones in the CP-115,955 series display higher activity against topoisomerase IIα in vitro and in cultured human cells than the corresponding quinazolinediones. Thus, quinolones may be a viable platform for the development of novel drugs with anticancer potential.

Mechanism of Action of Mycobacterium tuberculosis Gyrase Inhibitors: A Novel Class of Gyrase Poisons

“…15 Although clinically relevant fluoroquinolone antibacterials display low activity against the human type II enzymes, some members of this drug class cross over into mammalian systems and are potent poisons of human type II topoisomerases. 7, 10, 54–56 Because poisoning the human enzyme precludes the clinical use of these fluoroquinolones as antibacterial agents, it is important to assess the activity of gyrase-targeted drugs against the human enzymes.…”

The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity

“…In a recent investigation, the interaction of quinolones and type II topoisomerase of human and bacteria are mediated by different types of interactions. It was shown that the quinolones target the gyrase and topoisomerase-IV enzymes and inhibit bacterial growth [86]. These enzymes have the potential to fragment the cell genome, which is essential for cell survival and reproduction.…”

“…In addition, molecular docking and simulation of such structures and different quinolone analogues will be helpful in modelling the interactions to help design new drugs [83,84,96,97,98,99,100]. Osheroff and coworkers provided most of the data about the interaction of quinolones and topoisomerases [16,45,73,77,81,82,86,101,102,103,104,105,106,107,108,109]. In a recent study, the quinolone structure was placed near the serine and acidic residues, but it was found that the amino acids were not close enough to mediate a direct binding to drugs.…”

Treatment of human cells with 5-aza-dC induces formation of PARP1-DNA covalent adducts at genomic regions targeted by DNMT1

“…RADAR/slot blots [e.g. (Kiianitsa and Maizels, 2013;Aldred et al, 2015;Quinones et al, 2015;Vaz et al, 2016;Mohni et al, 2019)] probed with a mAb that recognizes an epitope in the catalytic domain of PARP1 (anti-cat-PARP1) showed that PARP1-DNA adducts were induced by treatment of either K562 or GM639 cells with 5-aza-dC ( Figure 3B).…”