New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens

DOI: 10.1016/j.ejmech.2021.113200

Authors: Martina Durcik (University of Ljubljana) , Ákos Nyerges (Biological Research Centre, Hungary) , Žiga Skok (University of Ljubljana) , Darja Gramec Skledar (University of Ljubljana) , Jurij Trontelj (University of Ljubljana) , Nace Zidar (University of Ljubljana) , Janez Ilaš (University of Ljubljana) , Anamarija Zega (University of Ljubljana) , Cristina D. Cruz (University of Helsinki) , Päivi Tammela (University of Helsinki) , Martin Welin (SARomics Biostructures) , Yengo R. Kimbung (SARomics Biostructures) , Dorota Focht (SARomics Biostructures) , Ondřej Benek (University of Hradec Kralove) , Tamás Révész (Biological Research Centre, Hungary) , Gábor Draskovits (Biological Research Centre, Hungary) , Petra Éva Szili (Biological Research Centre, Hungary) , Lejla Daruka (Biological Research Centre, Hungary) , Csaba Pál (Biological Research Centre, Hungary) , Danijel Kikelj (University of Ljubljana) , Lucija Peterlin Mašič (University of Ljubljana) , Tihomir Tomašič (University of Ljubljana)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 213

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 20028

Abstract: The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase Ⅳ offer an opportunity to accomplish this goal. Here we present the design and structure-activity relationship analysis of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens. For inhibitor 31c, a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compounds. The best inhibitor, 31h, does not show any in vitro cytotoxicity and has excellent potency against Gram-positive (MICs: range, 0.0078–0.0625 μg/mL) and Gram-negative pathogens (MICs: range, 1–2 μg/mL). Furthermore, 31h inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, we expect that structural derivatives of 31h will represent a step toward clinically efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance.

Journal Keywords: Dual inhibitor; DNA gyrase; Topoisomerase IV; Benzothiazole; Antibacterial

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-Macromolecular Crystallography

Added On: 31/01/2022 14:25

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)