Designing the DNA-intercalating moiety to improve the safety and efficacy of novel bacterial topoisomerase inhibitors

Zorman, Maša (author), Zajec, Živa (author), Zdovc, Irena (author), Šenerović, Lidija (author), Radakovic, Natasa (author), Atanasković, Marija (author), Anderluh, Marko (author), Minovski, Nikola (author), Hrast Rambaher, Martina (author)

Novel bacterial topoisomerase inhibitors (NBTIs) target bacterial topoisomerases through binding modes distinct from fluoroquinolones but are often limited by hERG channel inhibition. Our previous findings indicated that the introduction of a non-aminopiperidine linker and a halogenated phenyl enzyme-binding moiety can partially reduce cardiotoxicity. In this paper, we describe whether optimizing the DNA-intercalating 1,5-naphthyridine moiety could further improve safety while maintaining antibacterial potency. Several optimized compounds showed strong enzyme inhibition and potent antibacterial activity, particularly against Gram-positive pathogens. Compound 13 displayed broad-spectrum activity, with MICs as low as 0.008 μg/mL against Gram-positive and 0.125 μg/mL against Gram-negative bacteria. Safety profiling revealed reduced cytotoxicity and hERG binding compared to earlier series. Compounds 6, 20, 24, and 25 were nontoxic in zebrafish embryo assays. Compound 13 showed toxicity only at high doses and protected embryos in a lethal Staphylococcus aureus infection model, highlighting its potential as a preclinical lead.

• Language: English
• Keywords: bacteria, peptides and proteins, extraction, inhibition, nuclear magnetic resonance spectroscopy
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; VF - Veterinary Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: Str. 18117-18146
• Numbering: Vol. 69, iss. 15
• PID: 20.500.12556/RUL-189711
• UDC: 543.429.23:615
• ISSN on article: 1520-4804
• DOI: 10.1021/acs.jmedchem.6c00415
• COBISS.SI-ID: 286613763
• Publication date in RUL: 13.10.2026

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: bakterije, peptidi in proteini, ekstrakcija, inhibicija, spektroskopija jedrske magnetne resonance, jedrska magnetna resonanca, farmacevtska kemija