20.500.12556/RUL-144808 Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds 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. antibacterials DNA gyrase inhibitors drug discovery Staphylococcus aureus intercalators novel bacterial topoisomerase inhibitors NBTIs symmetrical bifurcated halogen bonds crystal structure novel NBTIs mechanism of action antimicrobials DNA-binding proteins drug development X-ray crystallography biokemija DNK Escherichia coli zaviralci true false true Angleški jezik Slovenski jezik Članek v reviji 2023-03-14 09:07:37 2023-03-14 09:07:42 2023-03-15 03:30:56 0000-00-00 00:00:00 2021 0 0 13 str. Vol. 12, art. 150 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577 2041-1723 10.1038/s41467-020-20405-8 46272259 s41467-020-20405-8.pdf s41467-020-20405-8.pdf 1 00DFF7317DB718CDA1A6E440A9F4B62B ee21233b41caa75bc221e514699b37252ed13c00a3f65ca1ad417af35cd5c40a 8fc0bdf5-c23f-11ed-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=167334 https://www.nature.com/articles/s41467-020-20405-8 1 3e5b2672-c23f-11ed-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=167333 Fakulteta za farmacijo 0 0 0