Inhibition of Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS): toward next-generation antituberculosis agents
Date
2021
Authors
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.
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Journal article
Citation
ACS Chemical Biology, 2021; 16(11):2339-2347
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
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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.
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© 2021 American Chemical Society