title: 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. On the basis of 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.
authors.affiliation: Department of Biochemistry and ⊥Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Aldred
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Schwanz
authors.forename: Gangqin
authors.initials: G
authors.lastname: Li
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Williamson
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: McPherson
authors.forename: Charles L
authors.initials: CL
authors.lastname: Turnbough
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kerns
authors.forename: Neil
authors.initials: N
authors.lastname: Osheroff
mesh_terms: D001408:Bacillus anthracis / Q000201:enzymology* / Q000235:genetics; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D024841:Fluoroquinolones / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; C076132:CP 115955; D027101:DNA Topoisomerase IV; D004250:DNA Topoisomerases, Type II