title: Network analysis identifies Rv0324 and Rv0880 as regulators of bedaquiline tolerance in Mycobacterium tuberculosis.
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.
authors: Institute for Systems Biology, Seattle, WA.
authors: Eliza J R
authors: EJR
authors: Peterson
authors: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, Seattle, WA.
authors: Shuyi
authors: S
authors: Ma
authors: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, Seattle, WA.|Interdisciplinary Program of Pathobiology, Department of Global Health, University of Washington, Seattle, WA.
authors: David R
authors: DR
authors: Sherman
authors: Institute for Systems Biology, Seattle, WA.|Molecular and Cellular Biology Program, Departments of Microbiology and Biology, University of Washington, Seattle, WA.|Lawrence Berkeley National Laboratories, Berkeley, CA.
authors: Nitin S
authors: NS
authors: Baliga
mesh_terms: D000995:Antitubercular Agents / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D064687:Diarylquinolines / Q000378:metabolism*; D004361:Drug Tolerance; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D064687:Diarylquinolines; C493870:bedaquiline