20.500.12556/RUL-145096 New dual inhibitors of bacterial topoisomerases with broad-spectrum antibacterial activity and in vivo efficacy against vancomycin-intermediate Staphylococcus aureus A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125–0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1–4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated. antibacterial activity bacteria inhibitors genetics inhibition peptides and proteins antibakterijsko delovanje zaviralci nanomolarni inhibitorji benzotiazola topoizomeraza IV farmacevtska kemija bakterije bakterijska rezistenca true false true Angleški jezik Slovenski jezik Članek v reviji 2023-04-05 09:53:35 2023-04-05 09:53:39 2023-04-08 03:40:02 0000-00-00 00:00:00 2023 0 0 Str. 3968-3994 iss. 6 Vol. 66 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.015.8 1520-4804 10.1021/acs.jmedchem.2c01905 144333571 acs.jmedchem.2c01905.pdf acs.jmedchem.2c01905.pdf 1 5DD9CC02507A37180CB47A24D863D63C 7166da01f45b7a2b5fe018508c23a3e67d8bee696a8353f07920482de87ca696 412e9ed4-d50a-11ed-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=167782 https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01905 1 dc3aa149-d386-11ed-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=167737 Fakulteta za farmacijo 0 0 0