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

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

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.

• Language: English
• Keywords: NBTIs, DNA gyrase, M. tuberculosis, crystal structure, bifurcated halogen bonds
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 2164−2170
• Numbering: Vol. 15, iss. 12
• PID: 20.500.12556/RUL-165967
• UDC: 615.4:54:616-002.5
• ISSN on article: 1948-5875
• DOI: 10.1021/acsmedchemlett.4c00447
• COBISS.SI-ID: 215946755
• Publication date in RUL: 16.12.2024

Record is a part of a journal

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

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