Baeyer-Villiger Monooxygenases EthA and MymA Are Required for Activation of Replicating and Non-replicating Mycobacterium tuberculosis Inhibitors.
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.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
Sarah Schmidt
SS
Grant
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
Samantha
S
Wellington
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
Tomohiko
T
Kawate
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Christopher A
CA
Desjardins
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Melanie R
MR
Silvis
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Carl
C
Wivagg
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Matthew
M
Thompson
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Katherine
K
Gordon
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Edward
E
Kazyanskaya
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Raymond
R
Nietupski
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Nathan
N
Haseley
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Noriaki
N
Iwase
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Ashlee M
AM
Earl
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Michael
M
Fitzgerald
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: hung@molbio.mgh.harvard.edu.
Deborah T
DT
Hung
D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D005000:Ethionamide / Q000737:chemistry / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development* / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D054852:Small Molecule Libraries; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; C480352:ethA protein, Mycobacterium tuberculosis; D005000:Ethionamide