Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds.

Anja Kolarič, Thomas Germe, Martina Hrast, Clare E M Stevenson, David M Lawson, Nicolas P Burton, Judit Vörös, Anthony Maxwell, Nikola Minovski, Marko Anderluh

Nature communications 2021 Jan 08

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Novel bacterial type II topoisomerase inhibitors (NBTIs) stabilize single-strand DNA cleavage breaks by DNA gyrase but their exact mechanism of action has remained hypothetical until now. We have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase-DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. This crystal stucture shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now.

Citation

Anja Kolarič, Thomas Germe, Martina Hrast, Clare E M Stevenson, David M Lawson, Nicolas P Burton, Judit Vörös, Anthony Maxwell, Nikola Minovski, Marko Anderluh. Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds. Nature communications. 2021 Jan 08;12(1):150