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https://hdl.handle.net/2440/132866
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Type: | Journal article |
Title: | Inhibition of Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS): toward next-generation antituberculosis agents |
Author: | Schumann, N.C. Lee, K.J. Thompson, A.P. Salaemae, W. Pederick, J.L. Avery, T. Gaiser, B.I. Hodgkinson-Bean, J. Booker, G.W. Polyak, S.W. Bruning, J.B. Wegener, K.L. Abell, A.D. |
Citation: | ACS Chemical Biology, 2021; 16(11):2339-2347 |
Publisher: | American Chemical Society |
Issue Date: | 2021 |
ISSN: | 1554-8929 1554-8937 |
Statement of Responsibility: | Nicholas 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 |
Abstract: | Mycobacterium 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. |
Keywords: | Mycobacterium tuberculosis Carbon-Nitrogen Ligases Enzyme Inhibitors Antitubercular Agents Crystallography, X-Ray Molecular Structure Protein Binding Drug Development |
Rights: | © 2021 American Chemical Society |
DOI: | 10.1021/acschembio.1c00491 |
Grant ID: | http://purl.org/au-research/grants/arc/CE140100003 |
Published version: | http://dx.doi.org/10.1021/acschembio.1c00491 |
Appears in Collections: | Chemistry publications |
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