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

Cotman, Andrej Emanuel (author), Durcik, Martina (author), Benedetto Tiz, Davide (author), Fulgheri, Federica (author), Secci, Daniela (author), Sterle, Maša (author), Možina, Štefan (author), Skok, Žiga (author), Zidar, Nace (author), Zega, Anamarija (author), Ilaš, Janez (author), Peterlin-Mašič, Lucija (author), Tomašič, Tihomir (author), Kikelj, Danijel (author)

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.

• Language: English
• Keywords: antibacterial activity, bacteria, genetics, inhibitors, solubility
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 1380–1425
• Numbering: Vol. 66, iss. 2
• PID: 20.500.12556/RUL-144326
• UDC: 615.015.8
• ISSN on article: 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01597
• COBISS.SI-ID: 138544899
• Publication date in RUL: 14.02.2023

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: antibakterijsko delovanje, zaviralci, topnost, genetika, bakterije, bakterijska rezistenca