Journal
MOLECULES
Volume 25, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/molecules25102384
Keywords
altholactone; tuberculosis; Rv1466; drug target; native mass spectrometry
Funding
- Bill and Melinda Gates Foundation [OPP1035218, OPP1174957]
- Australian Research Council [DP160101429, LP120100485, LE120100170, LE140100119]
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSH27220120025C, HHSN272200700057C, HHSN272201700059C]
- Bill and Melinda Gates Foundation [OPP1174957, OPP1035218] Funding Source: Bill and Melinda Gates Foundation
- Australian Research Council [LE140100119, LE120100170, LP120100485] Funding Source: Australian Research Council
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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 mu ge/mu L. A known compound, altholactone, was identified from this fraction that showed activity towards M. tuberculosis at an minimum inhibitory concentration (MIC) of 64 mu M. 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 mu M. Our findings established Rv1466 as the potential molecular target of altholactone, which is responsible for the observed in vivo toxicity towards M. tuberculosis.
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