The mechanistic basis of Artemisia annua activity against Mycobacterium tuberculosis

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Project summary/abstract Tuberculosis (TB) is difficult to treat in part because the bacterium that causes it, Mycobacterium tuberculosis, is not easily killed by antibiotics. Furthermore, M. tuberculosis easily acquires high-level drug resistance through mutations. As a consequence, six months or more of multi-drug treatment are required to fully cure a case of TB and prevent relapse. To combat drug resistance and shorten treatment regimens, there is need for new drugs, new targets, and improved understanding of the ways that drugs interact. Artemisia annua L. is a plant that is the source of the antimalarial drug artemisinin. We have found that extracts of A. annua have strong bactericidal activity against M. tuberculosis that cannot be fully explained by their artemisinin content. We therefore hypothesize that A. annua contains one or more additional compounds with antimycobacterial activity. To assess the potential of these compounds for development into TB drugs, we will (1) define the impact of A. annua extracts on M. tuberculosis gene expression, (2) select for and sequence resistant mutants, (3) determine how artemisinin and A. annua extracts interact with existing antimycobacterial agents, and (4) identify and isolate A. annua compounds responsible for bactericidal activity against M. tuberculosis. Completion of this work will identify A. annua compounds that exert antimycobacterial effects alone or in combination with each other or artemisinin, and shed light on the mechanism(s) of action of these compounds as well as their potential to synergize with existing drugs. The proposed studies will therefore provide foundational knowledge needed to identify and further develop scaffolds with therapeutic potential.