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Inhibition of Mycobacterium tuberculosis Dethiobiotin Synthase (MtDTBS): Toward Next-Generation Antituberculosis Agents
- Source :
- ACS Chemical Biology. 16:2339-2347
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
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 (KD = 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 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 KD = 19 ± 5 and 17 ± 1 μM, respectively. Further optimization identified tetrazole 7a as a particularly potent binder (KD = 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.
- Subjects :
- Tuberculosis
In silico
01 natural sciences
Biochemistry
Dethiobiotin synthase
Mycobacterium tuberculosis
03 medical and health sciences
chemistry.chemical_compound
Biotin
Biosynthesis
medicine
Tetrazole
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
biology
010405 organic chemistry
General Medicine
medicine.disease
biology.organism_classification
0104 chemical sciences
3. Good health
Enzyme
chemistry
biology.protein
Molecular Medicine
Subjects
Details
- ISSN :
- 15548937 and 15548929
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- ACS Chemical Biology
- Accession number :
- edsair.doi...........5ac2bc6435643604f3c068bed34da81f