Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa

• Published in: Journal of medicinal chemistry 2023-01, Vol.66 (2), p.1380-1425
• Main Authors: Cotman, Andrej Emanuel, Durcik, Martina, Benedetto Tiz, Davide, Fulgheri, Federica, Secci, Daniela, Sterle, Maša, Možina, Štefan, Skok, Žiga, Zidar, Nace, Zega, Anamarija, Ilaš, Janez, Peterlin Mašič, Lucija, Tomašič, Tihomir, Hughes, Diarmaid, Huseby, Douglas L., Cao, Sha, Garoff, Linnéa, Berruga Fernández, Talía, Giachou, Paraskevi, Crone, Lisa, Simoff, Ivailo, Svensson, Richard, Birnir, Bryndis, Korol, Sergiy V., Jin, Zhe, Vicente, Francisca, Ramos, Maria C., de la Cruz, Mercedes, Glinghammar, Björn, Lenhammar, Lena, Henderson, Sara R., Mundy, Julia E. A., Maxwell, Anthony, Stevenson, Clare E. M., Lawson, David M., Janssen, Guido V., Sterk, Geert Jan, Kikelj, Danijel
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii; Acinetobacter baumannii - metabolism; Anti-Bacterial Agents; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antiinfective agent; benzothiazole derivative; Benzothiazoles; chemistry; DNA Gyrase; DNA Gyrase - metabolism; DNA topoisomerase (ATP hydrolysing); Escherichia coli; Escherichia coli - metabolism; gyrase inhibitor; human; Humans; metabolism; microbial sensitivity test; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas aeruginosa - metabolism; Topoisomerase II Inhibitors; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01597

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.