Article Metrics


Online attention

Discovery and hit-to-lead optimization of benzothiazole scaffold-based DNA gyrase inhibitors with potent activity against Acinetobacter baumannii and Pseudomonas aeruginosa

DOI: 10.1021/acs.jmedchem.2c01597 DOI Help

Authors: Andrej Emanuel Cotman (University of Ljubljana) , Martina Durcik (University of Ljubljana) , Davide Benedetto Tiz (University of Ljubljana) , Federica Fulgheri (University of Ljubljana) , Daniela Secci (University of Ljubljana) , Maša Sterle (University of Ljubljana) , Štefan Možina (University of Ljubljana) , Žiga Skok (University of Ljubljana) , Nace Zidar (University of Ljubljana) , Anamarija Zega (University of Ljubljana) , Janez Ilaš (University of Ljubljana) , Lucija Peterlin Mašič (University of Ljubljana) , Tihomir Tomašič (University of Ljubljana) , Diarmaid Hughes (Uppsala University) , Douglas L. Huseby (Uppsala University) , Sha Cao (Uppsala University) , Linnéa Garoff (Uppsala University) , Talía Berruga Fernández (Uppsala University) , Paraskevi Giachou (Uppsala University) , Lisa Crone (Uppsala University) , Ivailo Simoff (Uppsala University) , Richard Svensson (Uppsala University) , Bryndis Birnir (Uppsala University) , Sergiy V. Korol (Uppsala University) , Zhe Jin (Uppsala University) , Francisca Vicente (Fundación MEDINA) , Maria C. Ramos (Fundación MEDINA) , Mercedes De La Cruz (Fundación MEDINA) , Björn Glinghammar (RISE Research Institutes of Sweden,) , Lena Lenhammar (Uppsala University) , Sara R. Henderson (John Innes Centre) , Julia E. A. Mundy (John Innes Centre) , Anthony Maxwell (John Innes Centre) , Claren E. M. Stevenson (John Innes Centre) , David M. Lawson (John Innes Centre) , Guido V. Janssen (rije Universiteit Amsterdam) , Geert Jan Sterk (Vrije Universiteit Amsterdam) , Danijel Kikelj (University of Ljubljana)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: January 2023
Diamond Proposal Number(s): 18565 , 25108

Open Access Open Access

Abstract: We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.

Diamond Keywords: Bacteria

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

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 16/01/2023 09:03


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)