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

Abstract

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 IC50 for M. tuberculosis gyrase of 0.096 μM, and it has potent activity against M. tuberculosis, with an IC50 of 0.165 μM.

Keywords

DNA giraza;Mycobacterium tuberculosis;inhibitorji;bakterijske topoizomeraze;NBTIs;DNA gyrase;M. tuberculosis;crystal structure;bifurcated halogen bonds;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.4:54:616-002.5
COBISS: 215946755 Link will open in a new window
ISSN: 1948-5875
Views: 30
Downloads: 15
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Other data

Secondary language: Slovenian
Secondary keywords: Farmacevtska kemija;Tuberkuloza;
Type (COBISS): Article
Pages: str. 2164-2170
Volume: ǂVol. ǂ15
Issue: ǂiss. ǂ12
Chronology: 2024
DOI: 10.1021/acsmedchemlett.4c00447
ID: 25518678