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Exploring the 5-substituted 2-aminobenzothiazole-based DNA Gyrase B inhibitors active against ESKAPE pathogens

DOI: 10.1021/acsomega.3c01930 DOI Help

Authors: Maša Sterle (University of Ljubljana) , Martina Durcik (University of Ljubljana) , Clare E. M. Stevenson (John Innes Centre) , Sara Henderson (University of Birmingham) , Petra Eva Szili (Institute of Biochemistry (Hungary)) , Marton Czikkely (Institute of Biochemistry (Hungary)) , David M. Lawson (John Innes Centre) , Anthony Maxwell (John Innes Centre) , Dominique Cahard (CNRS UMR 6014 COBRA, Normandie Université) , Danijel Kikelj (University of Ljubljana) , Nace Zidar (University of Ljubljana) , Csaba Pal (Institute of Biochemistry (Hungary)) , Lucija Peterlin Mašič (University of Ljubljana) , Janez Ilaš (University of Ljubljana) , Tihomir Tomašič (University of Ljubljana) , Andrej Emanuel Cotman (University of Ljubljana) , Anamarija Zega (University of Ljubljana)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Omega

State: Published (Approved)
Published: June 2023
Diamond Proposal Number(s): 18565

Open Access Open Access

Abstract: We present a new series of 2-aminobenzothiazole-based DNA gyrase B inhibitors with promising activity against ESKAPE bacterial pathogens. Based on the binding information extracted from the cocrystal structure of DNA gyrase B inhibitor A, in complex with Escherichia coli GyrB24, we expanded the chemical space of the benzothiazole-based series to the C5 position of the benzothiazole ring. In particular, compound E showed low nanomolar inhibition of DNA gyrase (IC50 < 10 nM) and broad-spectrum antibacterial activity against pathogens belonging to the ESKAPE group, with the minimum inhibitory concentration < 0.03 μg/mL for most Gram-positive strains and 4–16 μg/mL against Gram-negative E. coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. To understand the binding mode of the synthesized inhibitors, a combination of docking calculations, molecular dynamics (MD) simulations, and MD-derived structure-based pharmacophore modeling was performed. The computational analysis has revealed that the substitution at position C5 can be used to modify the physicochemical properties and antibacterial spectrum and enhance the inhibitory potency of the compounds. Additionally, a discussion of challenges associated with the synthesis of 5-substituted 2-aminobenzothiazoles is presented.

Diamond Keywords: Bacteria

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


Instruments: I03-Macromolecular Crystallography

Added On: 03/07/2023 08:17

Documents:
acsomega.3c01930.pdf

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)