biostudies-literatureDurcik MNational Academy of SciencesInnovative Medicines InitiativeH2020 European Institute of Innovation and TechnologyJavna Agencija za Raziskovalno Dejavnost RSDBT/Wellcome Trust India AllianceRedx Pharma PlcNemzeti Kutatási Fejlesztési és Innovációs HivatalEuropean Federation of Pharmaceutical Industries and AssociationsEuropean Research CouncilNational Laboratory of BiotechnologySeventh Framework ProgrammeELKH Lendület ProgrammeWellcome TrustBiotechnology and Biological Sciences Research Council3968-3994https://www.ebi.ac.uk/biostudies/studies/S-EPMC10041525biostudies-literatureUnknown66(6)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 <i>Enterococcus faecalis</i>, <i>Enterococcus faecium</i> and multidrug resistant (MDR) <i>Staphylococcus aureus</i> strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives <i>Acinetobacter baumannii</i> and <i>Klebsiella pneumoniae</i> (best compound MICs: range, 1-4 μg/mL). Lead compound <b>7a</b> was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of <b>7a</b> in complex wiJournal of medicinal chemistryNew Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate <i>Staphylococcus aureus</i>.PMC10041525FP7/2007-2013110072/Z/15/ZBI-HU/19-20-008NKFIH-871-3/2020LP-201710/20202022-2.1.1-NL-2022-00008648364BB/J014524/1BBS/E/J/000CA547115583P1-0208BB/P012523/1KKP 126506BBS/E/J/000PR9791J1-3030J1-3031Trontelj JSterk GJDurcik MMaharramov EKikelj DAlver SMundy JEACzikkely MPal CToplak ZVicente FBerruga-Fernandez TZega AMaxwell AZidar NHughes DJanssen GVTomasic TPiras MVPardo LAStevenson CEMVu THPeterlin Masic LJin ZLawson DMIlas JMozina SHuseby DSkok ZGlinghammar BCao SSvensson RCotman AEKorol SVRamos MCSimoff ISjostrom EOreskar JSzili PEBohlin MfalseNew Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate <i>Staphylococcus aureus</i>.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 <i>Enterococcus faecalis</i>, <i>Enterococcus faecium</i> and multidrug resistant (MDR) <i>Staphylococcus aureus</i> strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives <i>Acinetobacter baumannii</i> and <i>Klebsiella pneumoniae</i> (best compound MICs: range, 1-4 μg/mL). Lead compound <b>7a</b> was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of <b>7a</b> in complex wi2023-01-01T00:00:00Z2023 Mar2026-05-28T22:40:17.661Z2024-11-06T04:39:00.732ZS-EPMC100415253687725510.1021/acs.jmedchem.2c01905