20.500.12556/RUL-135734 A fine-tuned lipophilicity/hydrophilicity ratio governs antibacterial potency and selectivity of bifurcated halogen bond-forming NBTIs Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against some of the most concerning hard-to-treat pathogens for which new antibacterials are urgently needed, as reported by the WHO and CDC. NBTIs enzyme activity and whole cell potency seems to depend on the fine-tuned lipophilicity/hydrophilicity ratio that governs the permeability of those compounds through the bacterial membranes. Lipophilicity of NBTIs is apparently optimal for passing through the membrane of Gram-positive bacteria, but the higher, although not excessive lipophilicity and suitable hydrophilicity seems to determine the passage through Gram-negative bacterial membranes. However, due to the considerable hERG inhibition, which is still at least two orders of magnitude away from MICs, continued optimization is required to realize their full potential. antibacterials drug discovery DNA gyrase inhibitors topoisomerase IV inhibitors intercalators novel bacterial topoisomerase inhibitors topoisomerase II inhibitors intercalating agents farmacevtska kemija antibakterijska sredstva raziskave zdravil zaviralci DNA giraz zaviralci topoizomeraze IV interkalator novi zaviralci bakterijske topoizomeraze true false true Angleški jezik Slovenski jezik Članek v reviji 2022-03-30 09:05:26 2022-03-30 09:05:33 2022-09-14 04:14:53 0000-00-00 00:00:00 2021 0 0 30 str. iss. 7, art. 862 Vol. 10 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 2079-6382 10.3390/antibiotics10070862 70416899 RAZ_Kolaric_Anja_2021.pdf RAZ_Kolaric_Anja_2021.pdf 1 C6A4A8BB3E40F7F5C3A9AF9F40B7BC98 1fb404ffbc1a0ddcb30b6c5e42b014464eb2e324934fc2f929c4654b461bdbda 26a76f12-aff8-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=154996 https://www.mdpi.com/2079-6382/10/7/862 1 c6074dd9-aff7-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=154995 Fakulteta za farmacijo Veterinarska fakulteta 0 0 0