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.2021-10-292021-10-292021ACS Chemical Biology, 2021; 16(11):2339-23471554-89291554-8937https://hdl.handle.net/2440/132866Mycobacterium 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.en© 2021 American Chemical SocietyMycobacterium tuberculosisCarbon-Nitrogen LigasesEnzyme InhibitorsAntitubercular AgentsCrystallography, X-RayMolecular StructureProtein BindingDrug DevelopmentJournal article10.1021/acschembio.1c004912021-10-29588257Schumann, N.C. [0000-0002-6165-9066]Lee, K.J. [0000-0003-3006-5094]Pederick, J.L. [0000-0003-4048-9771]Avery, T. [0000-0001-6882-5461]Booker, G.W. [0000-0001-7207-4699]Polyak, S.W. [0000-0002-8458-5194]Bruning, J.B. [0000-0002-6919-1824]Wegener, K.L. [0000-0002-1562-6060]Abell, A.D. [0000-0002-0604-2629]