Inhibition of Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS): toward next-generation antituberculosis agents

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dc.contributor.authorSchumann, N.C.
dc.contributor.authorLee, K.J.
dc.contributor.authorThompson, A.P.
dc.contributor.authorSalaemae, W.
dc.contributor.authorPederick, J.L.
dc.contributor.authorAvery, T.
dc.contributor.authorGaiser, B.I.
dc.contributor.authorHodgkinson-Bean, J.
dc.contributor.authorBooker, G.W.
dc.contributor.authorPolyak, S.W.
dc.contributor.authorBruning, J.B.
dc.contributor.authorWegener, K.L.
dc.contributor.authorAbell, A.D.
dc.date.issued2021
dc.description.abstractMycobacterium tuberculosis dethiobiotin synthase (MtDTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, M. tuberculosis. Here, we report a binder of MtDTBS, cyclopentylacetic acid 2 (K(D) = 3.4 ± 0.4 mM), identified viain silico screening. X-ray crystallography showed that 2 binds in the 7,8-diaminopelargonic acid (DAPA) pocket of MtDTBS. Appending an acidic group to the para-position of the aromatic ring of the scaffold revealed compounds 4c and 4d as more potent binders, with K(D) = 19 ± 5 and 17 ± 1 μM, respectively. Further optimization identified tetrazole 7a as a particularly potent binder (K(D) = 57 ± 5 nM) and inhibitor (Ki = 5 ± 1 μM) of MtDTBS. Our findings highlight the first reported inhibitors of MtDTBS and serve as a platform for the further development of potent inhibitors and novel therapeutics for the treatment of tuberculosis.
dc.description.statementofresponsibilityNicholas C. Schumann, Kwang Jun Lee, Andrew P. Thompson, Wanisa Salaemae, Jordan L. Pederick, Thomas Avery, Birgit I. Gaiser, James Hodgkinson-Bean, Grant W. Booker, Steven W. Polyak, John B. Bruning, Kate L. Wegener, and Andrew D. Abell
dc.identifier.citationACS Chemical Biology, 2021; 16(11):2339-2347
dc.identifier.doi10.1021/acschembio.1c00491
dc.identifier.issn1554-8929
dc.identifier.issn1554-8937
dc.identifier.orcidSchumann, N.C. [0000-0002-6165-9066]
dc.identifier.orcidLee, K.J. [0000-0003-3006-5094]
dc.identifier.orcidPederick, J.L. [0000-0003-4048-9771]
dc.identifier.orcidAvery, T. [0000-0001-6882-5461]
dc.identifier.orcidBooker, G.W. [0000-0001-7207-4699]
dc.identifier.orcidPolyak, S.W. [0000-0002-8458-5194]
dc.identifier.orcidBruning, J.B. [0000-0002-6919-1824]
dc.identifier.orcidWegener, K.L. [0000-0002-1562-6060]
dc.identifier.orcidAbell, A.D. [0000-0002-0604-2629]
dc.identifier.urihttps://hdl.handle.net/2440/132866
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.relation.granthttp://purl.org/au-research/grants/arc/CE140100003
dc.rights© 2021 American Chemical Society
dc.source.urihttps://doi.org/10.1021/acschembio.1c00491
dc.subjectMycobacterium tuberculosis
dc.subjectCarbon-Nitrogen Ligases
dc.subjectEnzyme Inhibitors
dc.subjectAntitubercular Agents
dc.subjectCrystallography, X-Ray
dc.subjectMolecular Structure
dc.subjectProtein Binding
dc.subjectDrug Development
dc.titleInhibition of Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS): toward next-generation antituberculosis agents
dc.typeJournal article
pubs.publication-statusPublished

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