2. Academic Validation
  3. New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

  • J Med Chem. 2023 Mar 23;66(6):3968-3994. doi: 10.1021/acs.jmedchem.2c01905.
Martina Durcik 1,  Andrej Emanuel Cotman 1,  Žan Toplak 1,  Štefan Možina 1,  Žiga Skok 1,  Petra Eva Szili 2,  Márton Czikkely 2,  Elvin Maharramov 2,  Thu Hien Vu 2,  Maria Vittoria Piras 1,  Nace Zidar 1,  Janez Ilaš 1,  Anamarija Zega 1,  Jurij Trontelj 1,  Luis A Pardo 3,  Diarmaid Hughes 4,  Douglas Huseby 4,  Tália Berruga-Fernández 4,  Sha Cao 4,  Ivailo Simoff 5,  Richard Svensson 5,  Sergiy V Korol 6,  Zhe Jin 6,  Francisca Vicente 7,  Maria C Ramos 7,  Julia E A Mundy 8,  Anthony Maxwell 8,  Clare E M Stevenson 8,  David M Lawson 8,  Björn Glinghammar 9,  Eva Sjöström 10,  Martin Bohlin 10,  Joanna Oreskär 10,  Sofie Alvér 10,  Guido V Janssen 11,  Geert Jan Sterk 11,  Danijel Kikelj 1,  Csaba Pal 2,  Tihomir Tomašič 1,  Lucija Peterlin Mašič 1
Affiliations

Affiliations

  • 1 Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana 1000, Slovenia.
  • 2 Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged H-6726, Hungary.
  • 3 Max Planck Institute for Multidisciplinary Sciences, Oncophysiology, Hermann-Rein-Str. 3, Göttingen 37075, Germany.
  • 4 Department of Medical Biochemistry and Microbiology, Uppsala University, Husargatan 3, Uppsala 75123, Sweden.
  • 5 Drug Optimization and Pharmaceutical Profiling Platform (UDOPP) Department of Pharmacy, Uppsala University, Husargatan 3, Uppsala 75123, Sweden.
  • 6 Department of Medical Cell Biology, Uppsala University, Husargatan 3, Uppsala 75123, Sweden.
  • 7 Fundación Medina, Avenida del Conocimiento 34, Parque Tecnológico Ciencias de la Salud, Granada 18016, Spain.
  • 8 Department of Biochemistry and Metabolism, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, U.K.
  • 9 Department of Chemical and Pharmaceutical Toxicology, RISE Research Institutes of Sweden, Södertälje 15136, Sweden.
  • 10 Department of Chemical Processes and Pharmaceutical Development, RISE Research Institutes of Sweden, Södertälje 15136, Sweden.
  • 11 Medicinal Chemistry Division, Vrije Universiteit Amsterdam, De Boelelaan 1108, Amsterdam 1081 HZ, The Netherlands.
PMID: 36877255 DOI: 10.1021/acs.jmedchem.2c01905
Abstract

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.

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