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


ABSTRACT: 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.

SUBMITTER: Kolaric A 

PROVIDER: S-EPMC7794245 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Kolarič Anja A   Germe Thomas T   Hrast Martina M   Stevenson Clare E M CEM   Lawson David M DM   Burton Nicolas P NP   Vörös Judit J   Maxwell Anthony A   Minovski Nikola N   Anderluh Marko M  

Nature communications 20210108 1


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  ...[more]

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