title: Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance.
abstract: Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion. This provides a molecular basis for the quinolone inhibition mechanism, resistance mutations and invariant quinolone antibacterial structural features.
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Wohlkonig
authors.forename: Pan F
authors.initials: PF
authors.lastname: Chan
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fosberry
authors.forename: Paul
authors.initials: P
authors.lastname: Homes
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Michael
authors.initials: M
authors.lastname: Kranz
authors.forename: Vaughan R
authors.initials: VR
authors.lastname: Leydon
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Miles
authors.forename: Neil D
authors.initials: ND
authors.lastname: Pearson
authors.forename: Rajika L
authors.initials: RL
authors.lastname: Perera
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Shillings
authors.forename: Michael N
authors.initials: MN
authors.lastname: Gwynn
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Bax
mesh_terms: D040981:Acinetobacter baumannii / Q000201:enzymology*; D027101:DNA Topoisomerase IV / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D015363:Quinolones; D027101:DNA Topoisomerase IV
references.citation: Antimicrob Agents Chemother. 1991 Aug;35(8):1647-50
references.pmid: 1656869
references.citation: Nat Rev Drug Discov. 2007 Jan;6(1):29-40
references.pmid: 17159923
references.citation: Chem Rev. 2005 Feb;105(2):559-92
references.pmid: 15700957
references.citation: Nat Struct Mol Biol. 2009 Jun;16(6):667-9
references.pmid: 19448616
references.citation: J Inorg Biochem. 2006 Nov;100(11):1755-63
references.pmid: 16934331
references.citation: Nucleic Acids Res. 2007;35(18):6075-85
references.pmid: 17766248
references.citation: Nature. 2007 Dec 20;450(7173):1201-5
references.pmid: 18097402
references.citation: Clin Infect Dis. 2009 Jan 1;48(1):1-12
references.pmid: 19035777
references.citation: PLoS One. 2010 Jun 30;5(6):e11388
references.pmid: 20613983
references.citation: J Mol Biol. 2001 Aug 3;311(1):195-203
references.pmid: 11469868