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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
Mode-of-action profiling reveals glutamine synthetase as a collateral metabolic vulnerability of M. tuberculosis to bedaquiline
Proceedings of the National Academy of Sciences of the United States of America, Volume 116, No. 39, Year 2019
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Description
Combination chemotherapy can increase treatment efficacy and suppress drug resistance. Knowledge of how to engineer rational, mechanism-based drug combinations, however, remains lacking. Although studies of drug activity have historically focused on the primary drug-target interaction, growing evidence has emphasized the importance of the subsequent consequences of this interaction. Bedaquiline (BDQ) is the first new drug for tuberculosis (TB) approved in more than 40 y, and a species-selective inhibitor of the Mycobacterium tuberculosis (Mtb) ATP synthase. Curiously, BDQ-mediated killing of Mtb lags significantly behind its inhibition of ATP synthase, indicating a mode of action more complex than the isolated reduction of ATP pools. Here, we report that BDQ-mediated inhibition of Mtb's ATP synthase triggers a complex metabolic response indicative of a specific hierarchy of ATP-dependent reactions. We identify glutamine synthetase (GS) as an enzyme whose activity is most responsive to changes in ATP levels. Chemical supplementation with exogenous glutamine failed to affect BDQ's antimycobacterial activity. However, further inhibition of Mtb's GS synergized with and accelerated the onset of BDQ-mediated killing, identifying Mtb's glutamine synthetase as a collateral, rather than directly antimycobacterial, metabolic vulnerability of BDQ. These findings reveal a previously unappreciated physiologic specificity of ATP and a facet of mode-of-action biology we term collateral vulnerability, knowledge of which has the potential to inform the development of rational, mechanism-based drug combinations. © 2019 National Academy of Sciences. All rights reserved.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC6765305/bin/pnas.1907946116.sapp.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC6765305/bin/pnas.1907946116.sd01.xlsx
https://efashare.b-cdn.net/share/pmc/articles/PMC6765305/bin/pnas.1907946116.sd02.xlsx
https://efashare.b-cdn.net/share/pmc/articles/PMC6765305/bin/pnas.1907946116.sd03.xlsx
https://efashare.b-cdn.net/share/pmc/articles/PMC6765305/bin/pnas.1907946116.sd04.xlsx
https://efashare.b-cdn.net/share/pmc/articles/PMC6765305/bin/pnas.1907946116.sd05.xlsx
https://efashare.b-cdn.net/share/pmc/articles/PMC6765305/bin/pnas.1907946116.sd06.xlsx
Authors & Co-Authors
Wang, Zhe
United States, New York
Weill Cornell Medicine
Marriner, Gwendolyn A.
United States, Bethesda
National Institutes of Health Nih
Boshoff, Helena Ingrid M.
United States, Bethesda
National Institutes of Health Nih
Barry, Clifton Earl
United States, Bethesda
National Institutes of Health Nih
Rhee, Kyu Y.
United States, New York
Weill Cornell Medicine
Statistics
Citations: 29
Authors: 5
Affiliations: 3
Identifiers
Doi:
10.1073/pnas.1907946116
ISSN:
00278424
Research Areas
Cancer
Infectious Diseases
Noncommunicable Diseases