Discovery of a Natural Product That Binds to the Mycobacterium tuberculosis Protein Rv1466 Using Native Mass Spectrometry.

Autor: Elnaas AR; Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia., Grice D; Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia., Han J; Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia., Feng Y; Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia., Capua AD; Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia., Mak T; Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia., Laureanti JA; Physical and Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA 99354, USA., Buchko GW; Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA 99354, USA.; School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA., Myler PJ; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA 98109, USA., Cook G; Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand., Quinn RJ; Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia., Liu M; Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2020 May 21; Vol. 25 (10). Date of Electronic Publication: 2020 May 21.
DOI: 10.3390/molecules25102384
Abstrakt: Elucidation of the mechanism of action of compounds with cellular bioactivity is important for progressing compounds into future drug development. In recent years, phenotype-based drug discovery has become the dominant approach to drug discovery over target-based drug discovery, which relies on the knowledge of a specific drug target of a disease. Still, when targeting an infectious disease via a high throughput phenotypic assay it is highly advantageous to identifying the compound's cellular activity. A fraction derived from the plant Polyalthia sp. showed activity against Mycobacterium tuberculosis at 62.5 μge/μL. A known compound, altholactone, was identified from this fraction that showed activity towards M. tuberculosis at an minimum inhibitory concentration (MIC) of 64 μM. Retrospective analysis of a target-based screen against a TB proteome panel using native mass spectrometry established that the active fraction was bound to the mycobacterial protein Rv1466 with an estimated pseudo- K d of 42.0 ± 6.1 µM. Our findings established Rv1466 as the potential molecular target of altholactone, which is responsible for the observed in vivo toxicity towards M. tuberculosis .
Databáze: MEDLINE
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