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Cell Chem Biol DOI:10.1016/j.chembiol.2016.05.011

Baeyer-Villiger Monooxygenases EthA and MymA Are Required for Activation of Replicating and Non-replicating Mycobacterium tuberculosis Inhibitors.

Publication TypeJournal Article
Year of Publication2016
AuthorsGrant, SSchmidt, Wellington, S, Kawate, T, Desjardins, CA, Silvis, MR, Wivagg, C, Thompson, M, Gordon, K, Kazyanskaya, E, Nietupski, R, Haseley, N, Iwase, N, Earl, AM, Fitzgerald, M, Hung, DT
JournalCell Chem Biol
Volume23
Issue6
Pages666-77
Date Published2016 Jun 23
ISSN2451-9456
Abstract

Successful treatment of Mycobacterium tuberculosis infection typically requires a complex regimen administered over at least 6 months. Interestingly, many of the antibiotics used to treat M. tuberculosis are prodrugs that require intracellular activation. Here, we describe three small molecules, active against both replicating and non-replicating M. tuberculosis, that require activation by Baeyer-Villiger monooxygenases (BVMOs). Two molecules require BVMO EthA (Rv3854c) for activation and the third molecule requires the BVMO MymA (Rv3083). While EthA is known to activate the antitubercular drug ethionamide, this is the first description of MymA as an activating enzyme of a prodrug. Furthermore, we found that MymA also plays a role in activating ethionamide, with loss of MymA function resulting in ethionamide-resistant M. tuberculosis. These findings suggest overlap in function and specificity of the BVMOs in M. tuberculosis.

DOI10.1016/j.chembiol.2016.05.011
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27321573?dopt=Abstract

Alternate JournalCell Chem Biol
PubMed ID27321573
PubMed Central IDPMC4920728
Grant ListK08 AI085033 / AI / NIAID NIH HHS / United States