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 synerg

SUBMITTER: Peterson EJR 

PROVIDER: S-EPMC5010021 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature