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


ABSTRACT: 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 ?ge/?L. A known compound, altholactone, was identified from this fraction that showed activity towards M. tuberculosis at an minimum inhibitory concentration (MIC) of 64 ?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-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.

SUBMITTER: Elnaas AR 

PROVIDER: S-EPMC7288112 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Elnaas Ali R AR   Grice Darren D   Han Jianying J   Feng Yunjiang Y   Capua Angela Di AD   Mak Tin T   Laureanti Joseph A JA   Buchko Garry W GW   Myler Peter J PJ   Cook Gregory G   Quinn Ronald J RJ   Liu Miaomiao M  

Molecules (Basel, Switzerland) 20200521 10


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 ac  ...[more]

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