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

  • ACS Chem Biol. 2021 Nov 19;16(11):2339-2347. doi: 10.1021/acschembio.1c00491.
Nicholas C Schumann  1  2  3 ,  Kwang Jun Lee  1  2  3 ,  Andrew P Thompson  4 ,  Wanisa Salaemae  5 ,  Jordan L Pederick  6 ,  Thomas Avery  1  2  3 ,  Birgit I Gaiser  2 ,  James Hodgkinson-Bean  6 ,  Grant W Booker  6 ,  Steven W Polyak  6 ,  John B Bruning  6 ,  Kate L Wegener  6 ,  Andrew D Abell  1  2  3
Affiliations
  • 1. Department of Chemistry, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
  • 2. Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, SA 5005, Australia.
  • 3. Institute of Photonics and Advanced Sensing (IPAS), School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
  • 4. Alzheimer's Research UK Oxford Drug Discovery Institute, Centre for Medicines Discovery, University of Oxford, Oxford OX3 7DQ, United Kingdom.
  • 5. Biochemistry, Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand.
  • 6. Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
PMID: 34533923 DOI: 10.1021/acschembio.1c00491
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.

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