title: Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin.
abstract: New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a 'pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested.
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, USA.
authors.forename: Pan F
authors.initials: PF
authors.lastname: Chan
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Velupillai
authors.initials: V
authors.lastname: Srikannathasan
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, USA.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Cui
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fosberry
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, USA.
authors.forename: Minghua
authors.initials: M
authors.lastname: Gu
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Hann
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Hibbs
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Homes
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Ingraham
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Pizzollo
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Shen
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Shillings
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Claus E
authors.initials: CE
authors.lastname: Spitzfaden
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Tanner
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Theobald
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stavenger
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Bax
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Gwynn
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D027081:DNA Gyrase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D005047:Etoposide / Q000737:chemistry* / Q000494:pharmacology; D024841:Fluoroquinolones / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D000077266:Moxifloxacin; D013211:Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004269:DNA, Bacterial; D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D027081:DNA Gyrase; D000077266:Moxifloxacin