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

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Identification and validation of the mode of action of the chalcone anti-mycobacterial compounds. / Anagani, Bhavani; Singh, Jagbir; Bassin, Jatinder; Besra, Gurdyal; Benham, Christopher; Reddy, Tummala Rama Krishna; Cox, Jonathan; Goyal, Madhu.

In: The Cell Surface, Vol. 6, 100041, 18.05.2020.

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Anagani, Bhavani ; Singh, Jagbir ; Bassin, Jatinder ; Besra, Gurdyal ; Benham, Christopher ; Reddy, Tummala Rama Krishna ; Cox, Jonathan ; Goyal, Madhu. / Identification and validation of the mode of action of the chalcone anti-mycobacterial compounds. In: The Cell Surface. 2020 ; Vol. 6.

Bibtex

@article{cde42adda540493291671e46101af810,
title = "Identification and validation of the mode of action of the chalcone anti-mycobacterial compounds",
abstract = "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 {\textquoteleft}hit{\textquoteright} 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",
keywords = "Chalcones, Docking, InhA, MIC, Mycolic Acids, Tuberculosis",
author = "Bhavani Anagani and Jagbir Singh and Jatinder Bassin and Gurdyal Besra and Christopher Benham and Reddy, {Tummala Rama Krishna} and Jonathan Cox and Madhu Goyal",
note = "Funding Information: G.S.B is supported by The Medical Research Council ( MR/S000542/1 and MR/R001154/1 ). Funding Information: 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 ]. Publisher Copyright: {\textcopyright} 2020 ",
year = "2020",
month = may,
day = "18",
doi = "10.1016/j.tcsw.2020.100041",
language = "English",
volume = "6",
journal = "The Cell Surface",
issn = "2468-2330",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Identification and validation of the mode of action of the chalcone anti-mycobacterial compounds

AU - Anagani, Bhavani

AU - Singh, Jagbir

AU - Bassin, Jatinder

AU - Besra, Gurdyal

AU - Benham, Christopher

AU - Reddy, Tummala Rama Krishna

AU - Cox, Jonathan

AU - Goyal, Madhu

N1 - Funding Information: G.S.B is supported by The Medical Research Council ( MR/S000542/1 and MR/R001154/1 ). Funding Information: 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 ]. Publisher Copyright: © 2020

PY - 2020/5/18

Y1 - 2020/5/18

N2 - 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

AB - 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

KW - Chalcones

KW - Docking

KW - InhA

KW - MIC

KW - Mycolic Acids

KW - Tuberculosis

UR - http://www.scopus.com/inward/record.url?scp=85085342953&partnerID=8YFLogxK

U2 - 10.1016/j.tcsw.2020.100041

DO - 10.1016/j.tcsw.2020.100041

M3 - Article

C2 - 32743153

VL - 6

JO - The Cell Surface

JF - The Cell Surface

SN - 2468-2330

M1 - 100041

ER -