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dc.contributor.authorAnagani, Bhavani
dc.contributor.authorSingh, Jagbir
dc.contributor.authorBassin, Jatinder
dc.contributor.authorBesra, Gurdyal
dc.contributor.authorBenham, Christopher
dc.contributor.authorReddy, Tummala Rama Krishna
dc.contributor.authorCox, Jonathan
dc.contributor.authorGoyal, Madhu
dc.date.accessioned2020-05-23T00:11:19Z
dc.date.available2020-05-23T00:11:19Z
dc.date.issued2020-05-18
dc.identifier.citationAnagani , B , Singh , J , Bassin , J , Besra , G , Benham , C , Reddy , T R K , Cox , J & Goyal , M 2020 , ' Identification and validation of the mode of action of the chalcone anti-mycobacterial compounds ' , The Cell Surface , vol. 6 , 100041 . https://doi.org/10.1016/j.tcsw.2020.100041
dc.identifier.issn2468-2330
dc.identifier.urihttp://hdl.handle.net/2299/22748
dc.descriptionFunding 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
dc.description.abstractObjectives: 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 developmenten
dc.format.extent872731
dc.language.isoeng
dc.relation.ispartofThe Cell Surface
dc.subjectChalcones
dc.subjectDocking
dc.subjectInhA
dc.subjectMIC
dc.subjectMycolic Acids
dc.subjectTuberculosis
dc.subjectMolecular Biology
dc.subjectCell Biology
dc.subjectMicrobiology
dc.subjectApplied Microbiology and Biotechnology
dc.titleIdentification and validation of the mode of action of the chalcone anti-mycobacterial compoundsen
dc.contributor.institutionVeterinary Science
dc.contributor.institutionMicrobiology and Biotechnology
dc.contributor.institutionBiosciences Research Group
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionPsychopharmacology, Drug Misuse and Novel Psychoactive Substances Unit
dc.contributor.institutionCentre for Health Services and Clinical Research
dc.contributor.institutionBasic and Clinical Science Unit
dc.contributor.institutionTRP Ion channels
dc.contributor.institutionDepartment of Clinical, Pharmaceutical and Biological Science
dc.contributor.institutionCentre for Research in Mechanisms of Disease and Drug Discovery
dc.contributor.institutionCentre for Future Societies Research
dc.description.statusPeer reviewed
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85085342953&partnerID=8YFLogxK
rioxxterms.versionofrecord10.1016/j.tcsw.2020.100041
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue


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