20.500.12556/RUL-153515 Exploring alternative pathways to target bacterial type II topoisomerases using NBTI antibacterials: beyond halogen-bonding interactions Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibacterial agents that target bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Our recently disclosed crystal structure of an NBTI ligand in complex with DNA gyrase and DNA revealed that the halogen atom in the para position of the phenyl right hand side (RHS) moiety is able to establish strong symmetrical bifurcated halogen bonds with the enzyme; these are responsible for the excellent enzyme inhibitory potency and antibacterial activity of these NBTIs. To further assess the possibility of any alternative interactions (e.g., hydrogen-bonding and/or hydrophobic interactions), we introduced various non-halogen groups at the p-position of the phenyl RHS moiety. Considering the hydrophobic nature of amino acid residues delineating the NBTI’s binding pocket in bacterial topoisomerases, we demonstrated that designed NBTIs cannot establish any hydrogen-bonding interactions with the enzyme; hydrophobic interactions are feasible in all respects, while halogen-bonding interactions are apparently the most preferred. DNA gyrase topoisomerase IV antibacterial NBTIs halogen-bonding interactions hydrogen-bonding interactions van der Waals interactions true false true Angleški jezik Ni določen Neznano 2024-01-11 12:13:36 2024-01-11 12:13:42 2024-01-12 03:42:28 0000-00-00 00:00:00 2023 0 0 15 str. no. 5, art. 930 Vol. 12 2023 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 2023-01-01 579 2079-6382 10.3390/antibiotics12050930 153123075 exploring-zdovc.pdf exploring-zdovc.pdf 1 922703967B7B31758F4BE438780630C4 e7c83f46bbd7544bedd016e3a49a7a2b026f2559bafc686f6c4947be8b1d4c91 001a9eb4-b075-11ee-bd27-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=179546 https://www.mdpi.com/2079-6382/12/5/930 1 7ba61c56-b072-11ee-bd27-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=179545 Fakulteta za farmacijo Veterinarska fakulteta 0 0 0