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Inhibition of Mycobacterium tuberculosis Dethiobiotin Synthase ( Mt DTBS): Toward Next-Generation Antituberculosis Agents.
- Source :
-
ACS chemical biology [ACS Chem Biol] 2021 Nov 19; Vol. 16 (11), pp. 2339-2347. Date of Electronic Publication: 2021 Sep 17. - Publication Year :
- 2021
-
Abstract
- Mycobacterium tuberculosis dethiobiotin synthase ( Mt DTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, M. tuberculosis . Here, we report a binder of Mt DTBS, cyclopentylacetic acid 2 ( K <subscript>D</subscript> = 3.4 ± 0.4 mM), identified via in silico screening. X-ray crystallography showed that 2 binds in the 7,8-diaminopelargonic acid (DAPA) pocket of Mt DTBS. 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 <subscript>D</subscript> = 19 ± 5 and 17 ± 1 μM, respectively. Further optimization identified tetrazole 7a as a particularly potent binder ( K <subscript>D</subscript> = 57 ± 5 nM) and inhibitor ( K <subscript>i</subscript> = 5 ± 1 μM) of Mt DTBS. Our findings highlight the first reported inhibitors of Mt DTBS and serve as a platform for the further development of potent inhibitors and novel therapeutics for the treatment of tuberculosis.
- Subjects :
- Antitubercular Agents metabolism
Carbon-Nitrogen Ligases metabolism
Crystallography, X-Ray
Drug Development
Enzyme Inhibitors metabolism
Molecular Structure
Protein Binding
Antitubercular Agents chemistry
Antitubercular Agents pharmacology
Carbon-Nitrogen Ligases antagonists & inhibitors
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Mycobacterium tuberculosis enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 16
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 34533923
- Full Text :
- https://doi.org/10.1021/acschembio.1c00491