Structural aspects of Mycobacterium tuberculosis DNA gyrase targeted by novel bacterial topoisomerase inhibitors

Kokot, Maja (avtor), Hrast, Martina (avtor), Feng, Lipeng (avtor), Mitchenall, Lesley A (avtor), Lawson, David M. (avtor), Maxwell, Anthony (avtor), Parish, Tanya (avtor), Minovski, Nikola (avtor), Anderluh, Marko (avtor)

In this Letter, we present a small series of novel bacterial topoisomerase inhibitors (NTBIs) that exhibit both potent inhibition of Mycobacterium tuberculosis DNA gyrase and potent antimycobacterial activity. The disclosed crystal structure of M. tuberculosis DNA gyrase in complex with DNA and compound 5 from this NBTI series reveals the binding mode of an NBTI in the GyrA binding pocket and confirms the presence and importance of halogen bonding for the excellent on-target potency. In addition, we have shown that compound 5 is a promising M. tuberculosis DNA gyrase inhibitor, with an IC$_{50}$ for M. tuberculosis gyrase of 0.096 μM, and it has potent activity against M. tuberculosis, with an IC$_{50}$ of 0.165 μM.

• Jezik: Angleški jezik
• Ključne besede: NBTIs, DNA gyrase, M. tuberculosis, crystal structure, bifurcated halogen bonds
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: Str. 2164−2170
• Številčenje: Vol. 15, iss. 12
• PID: 20.500.12556/RUL-165967
• UDK: 615.4:54:616-002.5
• ISSN pri članku: 1948-5875
• DOI: 10.1021/acsmedchemlett.4c00447
• COBISS.SI-ID: 215946755
• Datum objave v RUL: 16.12.2024

Gradivo je del revije

• Naslov: ACS Medicinal Chemistry Letters
• Založnik: American Chemical Society
• ISSN: 1948-5875
• COBISS.SI-ID: 2959217

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: DNA giraza, Mycobacterium tuberculosis, inhibitorji, bakterijske topoizomeraze, farmacevtska kemija, tuberkuloza