New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate <i>Staphylococcus aureus</i>.
Durcik M, Cotman AE, Toplak Ž, Možina Š, Skok Ž, Szili PE, Czikkely M, Maharramov E, Vu TH, Piras MV, Zidar N, Ilaš J, Zega A, Trontelj J, Pardo LA, Hughes D, Huseby D, Berruga-Fernández T, Cao S, Simoff I, Svensson R, Korol SV, Jin Z, Vicente F, Ramos MC, Mundy JEA, Maxwell A, Stevenson CEM, Lawson DM, Glinghammar B, Sjöström E, Bohlin M, Oreskär J, Alvér S, Janssen GV, Sterk GJ, Kikelj D, Pal C, Tomašič T, Peterlin Mašič L.
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 with <i>Pseudomonas aeruginosa</i> GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of <b>7a</b> and <b>7h</b> showed potent antibacterial activity against over 100 MDR and non-MDR strains of <i>A. baumannii</i> and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of <b>7a</b> in a mouse model of vancomycin-intermediate <i>S. aureus</i> thigh infection was also demonstrated.