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

1
Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia
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Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
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Physical and Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA 99354, USA
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Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA 99354, USA
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School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
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Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA 98109, USA
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Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand
*
Author to whom correspondence should be addressed.
Academic Editors: Elisa Ovidi and Antonio Tiezzi
Molecules 2020, 25(10), 2384; https://doi.org/10.3390/molecules25102384
Received: 25 April 2020 / Revised: 14 May 2020 / Accepted: 18 May 2020 / Published: 21 May 2020
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-Kd 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. View Full-Text
Keywords: altholactone; tuberculosis; Rv1466; drug target; native mass spectrometry altholactone; tuberculosis; Rv1466; drug target; native mass spectrometry
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Elnaas, A.R.; Grice, D.; Han, J.; Feng, Y.; Capua, A.D.; Mak, T.; Laureanti, J.A.; Buchko, G.W.; Myler, P.J.; Cook, G.; Quinn, R.J.; Liu, M. Discovery of a Natural Product That Binds to the Mycobacterium tuberculosis Protein Rv1466 Using Native Mass Spectrometry. Molecules 2020, 25, 2384.

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