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

doi:10.1038/s41467-020-20405-8

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

Nat Commun. 2021 Jan 8;12(1):150. doi: 10.1038/s41467-020-20405-8.

Authors

Affiliations

¹ Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
³ Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.
⁴ Inspiralis Ltd., Innovation Centre, Norwich Research Park, Colney Lane, Norwich, NR4 7GJ, UK.
⁵ Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia. [email protected].
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alanine / chemistry
Alanine / metabolism
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Chlorine / metabolism*
Crystallography, X-Ray
DNA Gyrase / chemistry
DNA Gyrase / metabolism*
DNA Topoisomerases, Type II
DNA, Single-Stranded / metabolism
Drug Design
ERG1 Potassium Channel / metabolism
Escherichia coli / drug effects
Escherichia coli / enzymology
Hep G2 Cells
Human Umbilical Vein Endothelial Cells
Humans
Inhibitory Concentration 50
Microbial Sensitivity Tests
Molecular Docking Simulation
Poly-ADP-Ribose Binding Proteins / antagonists & inhibitors
Quinolines / chemistry
Quinolines / pharmacology
Staphylococcus aureus / drug effects
Staphylococcus aureus / enzymology
Topoisomerase II Inhibitors / chemistry
Topoisomerase II Inhibitors / pharmacology*

Substances

Anti-Bacterial Agents
DNA, Single-Stranded
ERG1 Potassium Channel
GSK299423
KCNH2 protein, human
Poly-ADP-Ribose Binding Proteins
Quinolines
Topoisomerase II Inhibitors
Chlorine
DNA Gyrase
DNA Topoisomerases, Type II
TOP2A protein, human
Alanine

Abstract

Publication types

MeSH terms

Substances

Grants and funding