Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance.
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.
Wohlkonig
Alexandre
A
Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
Chan
Pan F
PF
Fosberry
Andrew P
AP
Homes
Paul
P
Huang
Jianzhong
J
Kranz
Michael
M
Leydon
Vaughan R
VR
Miles
Timothy J
TJ
Pearson
Neil D
ND
Perera
Rajika L
RL
Shillings
Anthony J
AJ
Gwynn
Michael N
MN
Bax
Benjamin D
BD
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
D004791:Enzyme Inhibitors; D015363:Quinolones; D027101:DNA Topoisomerase IV
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