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ABSTRACT The resilience of _Mycobacterium tuberculosis_ (MTB) emerges from its ability to effectively counteract immunological, environmental and antitubercular challenges. Here, we

demonstrate that MTB can tolerate drug treatment by adopting a tolerant state that can be deciphered through systems analysis of its transcriptional responses. Specifically, we demonstrate

how treatment with the antitubercular drug bedaquiline activates a regulatory network that coordinates multiple resistance mechanisms to push MTB into a tolerant state. Disruption of this

network, by knocking out its predicted transcription factors, Rv0324 and Rv0880, significantly increased bedaquiline killing and enabled the discovery of a second drug, pretomanid, that

potentiated killing by bedaquiline. We demonstrate that the synergistic effect of this combination emerges, in part, through disruption of the tolerance network. We discuss how this network

strategy also predicts drug combinations with antagonistic interactions, potentially accelerating the discovery of new effective combination drug regimens for tuberculosis. Access through

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SIMILAR CONTENT BEING VIEWED BY OTHERS TRANSCRIPTIONAL REGULATOR-INDUCED PHENOTYPE SCREEN REVEALS DRUG POTENTIATORS IN _MYCOBACTERIUM TUBERCULOSIS_ Article 16 November 2020 _MYCOBACTERIUM

TUBERCULOSIS_ RV3160C IS A TETR-LIKE TRANSCRIPTIONAL REPRESSOR THAT REGULATES EXPRESSION OF THE PUTATIVE OXYGENASE RV3161C Article Open access 15 January 2021 TCRXY IS AN ACID-SENSING

TWO-COMPONENT TRANSCRIPTIONAL REGULATOR OF _MYCOBACTERIUM TUBERCULOSIS_ REQUIRED FOR PERSISTENT INFECTION Article Open access 22 February 2024 REFERENCES * Phillips, L. Infectious disease:

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(2003). Article  Google Scholar  Download references ACKNOWLEDGEMENTS The authors thank members of the Baliga and Sherman laboratories for discussions, T. Rustad, J. Winkler and S. Hobbs for

generating knockout and overexpressing strains, and Z. Simon, M. Sarvothama and R. Liao for technical help. Funding was provided by the National Institute of Allergy and Infectious Diseases

of the National Institutes of Health (U19 AI10676, U19 AI111276 and ISBpilot-10135) and the National Institute of General Medical Sciences of the National Institutes of Health

(P50GM076547). AUTHOR INFORMATION Author notes * Eliza J. R. Peterson and Shuyi Ma: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Institute for Systems Biology,

Seattle, 98109, Washington, USA Eliza J. R. Peterson & Nitin S. Baliga * Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, 98109,

Washington, USA Shuyi Ma & David R. Sherman * Department of Global Health, Interdisciplinary Program of Pathobiology, University of Washington, Seattle, 98195, Washington, USA David R.

Sherman * Departments of Microbiology and Biology, Molecular and Cellular Biology Program, University of Washington, Seattle, 98195, Washington, USA Nitin S. Baliga * Lawrence Berkeley

National Laboratories, Berkeley, 94720, California, USA Nitin S. Baliga Authors * Eliza J. R. Peterson View author publications You can also search for this author inPubMed Google Scholar *

Shuyi Ma View author publications You can also search for this author inPubMed Google Scholar * David R. Sherman View author publications You can also search for this author inPubMed Google

Scholar * Nitin S. Baliga View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS E.J.R.P. led the design and drafted the manuscript. E.J.R.P. and

S.M. generated results and analysed data. S.M. helped design the study and helped draft online methods. D.R.S. helped designed the study, discussed results and commented on the manuscript.

N.S.B. conceived of the study, discussed the results and drafted the manuscript. CORRESPONDING AUTHOR Correspondence to Nitin S. Baliga. ETHICS DECLARATIONS COMPETING INTERESTS The authors

declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary Figures 1-8 and Supplementary Tables 4 and 5. (PDF 2195 kb) SUPPLEMENTARY TABLES

Supplementary Tables 1–3 (XLSX 58 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Peterson, E., Ma, S., Sherman, D. _et al._ Network analysis

identifies Rv0324 and Rv0880 as regulators of bedaquiline tolerance in _Mycobacterium tuberculosis_. _Nat Microbiol_ 1, 16078 (2016). https://doi.org/10.1038/nmicrobiol.2016.78 Download

citation * Received: 04 September 2015 * Accepted: 27 April 2016 * Published: 06 June 2016 * DOI: https://doi.org/10.1038/nmicrobiol.2016.78 SHARE THIS ARTICLE Anyone you share the following

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