Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance

The structure of Moxifloxacin, a quinolone antibacterial, in complex with Acinetobacter baumannii topoisomerase IV and DNA now shows how the drug stacks between base pairs at the DNA cleavage site. Moxifloxacin contacts the protein through a non-catalytic Mg 2+ , and the structure gives insight into the mode of inhibition and possible basis of drug 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.