Identification and validation of the mode of action of the chalcone anti-mycobacterial compounds


Objectives The search for new TB drugs has become one of the great challenges for modern medicinal chemistry. An improvement in the outcomes of TB chemotherapy can be achieved by the development of new, shorter, cheap, safe and effective anti-TB regimens. Methods Chalcones (1a-1o) were synthesized and evaluated for their antimycobacterial activity against Mycobacterium bovis BCG using growth inhibition assays. Compound 1a was selected as a ‘hit’ compound. The mode of action of compound 1a, was identified by mycolic acid methyl esters (MAMEs) and fatty acid methyl esters (FAMEs) analysis using thin layer chromatography. Dose dependent experiments were conducted by over-expressing components of FAS-II in M. bovis BCG to confirm the target. Ligand binding using intrinsic tryptophan assay and molecular docking were used to further validate the target. Results MAMEs and FAMEs analysis showed dose-dependent reduction of MAMEs with the overall abundance of FAMEs suggesting that compound 1a targets mycolic acid biosynthesis. Direct binding of 1a to InhA was observed using an intrinsic tryptophan fluorescence binding assay, and a 2-fold IC50 shift was observed with an InhA overexpressing strain confirming InhA as the cellular target. Conclusion The chalcone 1a exhibits potent antimycobacterial activity, displays a good safety profile and is a direct inhibitor of InhA, a key component in mycolic acid synthesis, validating this series for further anti-TB drug development.

Publication DOI:
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
Additional Information: © 2020 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( Funding Information: G.S.B is supported by The Medical Research Council ( MR/S000542/1 and MR/R001154/1 ). J.A.G.C. is supported by the Academy of Medical Sciences /the British Heart Foundation /the Government Department of Business, Energy and Industrial Strategy / Global Challenges Research Fund /the Wellcome Trust Springboard Award [ SBF003\1088 ].
Uncontrolled Keywords: Chalcones,Docking,InhA,MIC,Mycolic Acids,Tuberculosis,Molecular Biology,Cell Biology,Microbiology,Applied Microbiology and Biotechnology
Publication ISSN: 2468-2330
Last Modified: 11 Dec 2023 08:28
Date Deposited: 26 May 2020 12:14
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Related URLs: https://linking ... 468233020300086 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2020-12-01
Published Online Date: 2020-05-18
Accepted Date: 2020-05-13
Authors: Anagani, B.
Singh, J.
Bassin, J.p.
Besra, G.s.
Benham, C.
Reddy, T.r.k.
Cox, J.A.G. (ORCID Profile 0000-0001-5208-4056)
Goyal, M.

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