Discovery of an isothiazolinone-containing antitubercular natural product Levesquamide

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dc.contributor.authorLiang, Libang
dc.contributor.authorHaltli, Bradley
dc.contributor.authorMarchbank, Douglas H.
dc.contributor.authorFischer, Maike
dc.contributor.authorKirby, Christopher W.
dc.contributor.authorCorrea, Hebelin
dc.contributor.authorClark, Trevor N.
dc.contributor.authorGray, Christopher A.
dc.contributor.authorKerr, Russell G.
dc.date.accessioned2024-07-15T15:22:09Z
dc.date.available2024-07-15T15:22:09Z
dc.date.issued2020-05-04
dc.description.abstractAntitubercular agent levesquamide is a new polyketide-nonribosomal peptide (PK-NRP) hybrid marine natural product isolated from Streptomyces sp. RKND-216. The structure contains a rare isothiazolinone moiety which has only been reported in collismycin SN. Structure elucidation by NMR spectroscopy was a significant challenge due to a deficiency of protons in this aromatic moiety. Therefore, the genome of Streptomyces sp. RKND-216 was sequenced to identify the levesquamide biosynthetic gene cluster (BGC). Analysis of the BGC provided structural insights and guided stable-isotope labeling experiments, which led to the assignment of the fused pyridine-isothiazolinone moiety. The BGC and the labeling experiments provide further insights into the biosynthetic origin of isothiazolinones. Levesquamide exhibited antimicrobial activity in the microplate alamarBlue assay (MABA) and low oxygen recovery assay (LORA) against Mycobacterium tuberculosis H37Rv with minimum inhibitory concentration (MIC) values of 9.65 and 22.28 µM, respectively. Similar activity was exhibited against rifampicin- and isoniazid-resistant M. tuberculosis strains with MIC values of 9.46 and 9.90 µM, respectively. This result suggests levesquamide has a different mode of action against M. tuberculosiscompared to the two first-line antitubercular drugs rifampicin and isoniazid. Furthermore, levesquamide shows no cytotoxicity against the Vero cell line, suggesting it may have a useful therapeutic window.
dc.description.copyrightThis document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in The Journal of Organic Chemistry, copyright © American Chemical Society after peer review. To access the final edited and published work see https://dx.doi.org/10.1021/acs.joc.0c00339
dc.identifier.issn1520-6904
dc.identifier.urihttps://unbscholar.lib.unb.ca/handle/1882/38035
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.relationInnovation PEI
dc.relationNatural Sciences and Engineering Council of Canada
dc.relationCanada Research Chair Program
dc.relationAtlantic Canada Opportunities Agency
dc.relationCanada Foundation for Innovation
dc.relationNautilus Biosciences Croda
dc.relationJeanne and Jean-Louis Lévesque Foundation
dc.relation.hasversionhttps://dx.doi.org/10.1021/acs.joc.0c00339
dc.rightshttp://purl.org/coar/access_right/c_abf2
dc.subject.disciplineChemistry
dc.titleDiscovery of an isothiazolinone-containing antitubercular natural product Levesquamide
dc.typejournal article
oaire.citation.endPage6462
oaire.citation.issue10
oaire.citation.startPage6450
oaire.citation.titleThe Journal of Organic Chemistry
oaire.citation.volume85
oaire.license.conditionother
oaire.versionhttp://purl.org/coar/version/c_ab4af688f83e57aa

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