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

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

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.

• Jezik: Angleški jezik
• Ključne besede: bacteria, peptides and proteins, extraction, inhibition, nuclear magnetic resonance spectroscopy
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; VF - Veterinarska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: Str. 18117-18146
• Številčenje: Vol. 69, iss. 15
• PID: 20.500.12556/RUL-189711
• UDK: 543.429.23:615
• ISSN pri članku: 1520-4804
• DOI: 10.1021/acs.jmedchem.6c00415
• COBISS.SI-ID: 286613763
• Datum objave v RUL: 13.10.2026

Gradivo je del revije

• Naslov: Journal of medicinal chemistry
• Skrajšan naslov: J. med. chem.
• Založnik: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: bakterije, peptidi in proteini, ekstrakcija, inhibicija, spektroskopija jedrske magnetne resonance, jedrska magnetna resonanca, farmacevtska kemija