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

Nicholas C Schumann; Kwang Jun Lee; Andrew P Thompson; Wanisa Salaemae; Jordan L Pederick; Thomas Avery; Birgit I Gaiser; James Hodgkinson-Bean; Grant W Booker; Steven W Polyak; John B Bruning; Kate L Wegener; Andrew D Abell

doi:10.1021/acschembio.1c00491

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. Epub 2021 Sep 17.

Authors

Nicholas C Schumann^{1

2

3}, Kwang Jun Lee^{1

2

3}, Andrew P Thompson⁴, Wanisa Salaemae⁵, Jordan L Pederick⁶, Thomas Avery^{1

2

3}, Birgit I Gaiser², James Hodgkinson-Bean⁶, Grant W Booker⁶, Steven W Polyak⁶, John B Bruning⁶, Kate L Wegener⁶, 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 (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 μM, respectively. Further optimization identified tetrazole 7a as a particularly potent binder (K_D = 57 ± 5 nM) and inhibitor (K_i = 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / chemistry*
Antitubercular Agents / metabolism
Antitubercular Agents / pharmacology*
Carbon-Nitrogen Ligases / antagonists & inhibitors*
Carbon-Nitrogen Ligases / metabolism
Crystallography, X-Ray
Drug Development
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Molecular Structure
Mycobacterium tuberculosis / enzymology*
Protein Binding

Substances

Antitubercular Agents
Enzyme Inhibitors
Carbon-Nitrogen Ligases
dethiobiotin synthetase