Network analysis identifies Rv0324 and Rv0880 as regulators of bedaquiline tolerance in Mycobacterium tuberculosis.
|Title||Network analysis identifies Rv0324 and Rv0880 as regulators of bedaquiline tolerance in Mycobacterium tuberculosis.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Peterson EJR, Ma S, Sherman DR, Baliga NS|
|Date Published||2016 Jun 06|
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.
|Alternate Journal||Nat Microbiol|
|PubMed Central ID||PMC5010021|
|Grant List||P50 GM076547 / GM / NIGMS NIH HHS / United States |
U19 AI106761 / AI / NIAID NIH HHS / United States
U19 AI111276 / AI / NIAID NIH HHS / United States