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New dual inhibitors of bacterial topoisomerases with broad-spectrum antibacterial activity and in vivo efficacy against vancomycin-intermediate Staphylococcus aureus

DOI: 10.1021/acs.jmedchem.2c01905 DOI Help

Authors: Martina Durcik (University of Ljubljana) , Andrej Emanuel Cotman (University of Ljubljana) , Žan Toplak (University of Ljubljana) , Štefan Možina (University of Ljubljana) , Žiga Skok (University of Ljubljana) , Petra Eva Szili (Biological Research Centre (Hungary)) , Márton Czikkely (Biological Research Centre (Hungary)) , Elvin Maharramov (Biological Research Centre (Hungary)) , Thu Hien Vu (Biological Research Centre (Hungary)) , Maria Vittoria Piras (University of Ljubljana) , Nace Zidar (University of Ljubljana) , Janez Ilaš (University of Ljubljana) , Anamarija Zega (University of Ljubljana) , Jurij Trontelj (University of Ljubljana) , Luis A. Pardo (Max Planck Institute for Multidisciplinary Sciences) , Diarmaid Hughes (Uppsala University) , Douglas Huseby (Uppsala University) , Tália Berruga-Fernández (Uppsala University) , Sha Cao (Uppsala University) , Ivailo Simoff (Uppsala University) , Richard Svensson (Uppsala University) , Sergiy V. Korol (Uppsala University) , Zhe Jin (Uppsala University) , Francisca Vicente (Fundación Medina) , Maria C. Ramos (Fundación Medina) , Julia E. A. Mundy (John Innes Centre) , Anthony Maxwell (John Innes Centre) , Clare E. M. Stevenson (John Innes Centre) , David M. Lawson (John Innes Centre) , Björn Glinghammar (RISE Research Institutes of Sweden) , Eva Sjöström (RISE Research Institutes of Sweden) , Martin Bohlin (RISE Research Institutes of Sweden) , Joanna Oreskär (RISE Research Institutes of Sweden) , Sofie Alvér (RISE Research Institutes of Sweden) , Guido V. Janssen (Vrije Universiteit Amsterdam) , Geert Jan Sterk (Vrije Universiteit Amsterdam) , Danijel Kikelj (University of Ljubljana) , Csaba Pal (Biological Research Centre (Hungary)) , Tihomir Tomašič (University of Ljubljana) , Lucija Peterlin Mašič (University of Ljubljana)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 1703

State: Published (Approved)
Published: March 2023
Diamond Proposal Number(s): 25108

Open Access Open Access

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.

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 07/03/2023 14:30


Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)