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Exploring the chemical space of benzothiazole-based DNA gyrase B inhibitors

DOI: 10.1021/acsmedchemlett.0c00416 DOI Help

Authors: Žiga Skok (University of Ljubljana) , Michaela Barančoková (University of Ljubljana) , Ondřej Benek (University of Hradec Kraĺove) , Cristina Durante Cruz (University of Helsinki) , Päivi Tammela (University of Helsinki) , Tihomir Tomašič (University of Ljubljana) , Nace Zidar (University of Ljubljana) , Lucija Peterlin Mašič (University of Ljubljana) , Anamarija Zega (University of Ljubljana) , Clare E. M. Stevenson (John Innes Centre) , Julia E. A. Mundy (John Innes Centre) , David M. Lawson (John Innes Centre) , Anthony Maxwell (John Innes Centre) , Danijel Kikelj (University of Ljubljana) , Janez Ilaš (University of Ljubljana)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: October 2020
Diamond Proposal Number(s): 18565

Open Access Open Access

Abstract: We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 μM), and efflux impaired E. coli strain (MIC = 0.78 μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.

Journal Keywords: DNA gyrase; topoisomerase; IV; GyrB; ParE; antibacterial; benzothiazole

Diamond Keywords: Enzymes; Bacteria

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

Instruments: I04-Macromolecular Crystallography

Added On: 19/10/2020 09:46


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)