Inhibition of Mycobacterium tuberculosis Dethiobiotin Synthase (MtDTBS): Toward Next-Generation Antituberculosis Agents

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, cydopentylacetic acid 2 (K-D = 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 K-D( )= 19 +/- 5 and 17 +/- 1 mu M, respectively. Further optimization identified tetrazole 7a as a particularly potent binder (K-D = 57 +/- 5 nM) and inhibitor (K-i = 5 +/- 1 mu M) 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.

Automated summary

Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS) inhibitor, cydopentylacetic acid 2, was identified through in silico screening, with further compounds showing increased binding potency. Tetrazole 7a was identified as a particularly potent binder and inhibitor of MtDTBS, providing a platform for the development of novel therapeutics for tuberculosis treatment.