Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/89326
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dc.contributorDepartment of Applied Biology and Chemical Technologyen_US
dc.creatorYe, Jen_US
dc.creatorChu, AJen_US
dc.creatorHarper, Ren_US
dc.creatorChan, STen_US
dc.creatorShek, TLen_US
dc.creatorZhang, Yen_US
dc.creatorIp, Men_US
dc.creatorSambir, Men_US
dc.creatorArtsimovitch, Ien_US
dc.creatorZuo, Zen_US
dc.creatorYang, Xen_US
dc.creatorMa, Cen_US
dc.date.accessioned2021-03-12T09:35:59Z-
dc.date.available2021-03-12T09:35:59Z-
dc.identifier.issn0022-2623en_US
dc.identifier.urihttp://hdl.handle.net/10397/89326-
dc.language.isoenen_US
dc.publisherAmerican Chemical Societyen_US
dc.rights© 2020 American Chemical Societyen US
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://dx.doi.org/10.1021/acs.jmedchem.0c00520.en US
dc.rightsJournal of Medicinal Chemistry is available at https://pubs.acs.org/journal/jmcmar.en US
dc.titleDiscovery of antibacterials that inhibit bacterial RNA polymerase interactions with sigma factorsen_US
dc.typeJournal/Magazine Articleen_US
dc.identifier.spage7695en_US
dc.identifier.epage7720en_US
dc.identifier.volume63en_US
dc.identifier.issue14en_US
dc.identifier.doi10.1021/acs.jmedchem.0c00520en_US
dcterms.abstractFormation of a bacterial RNA polymerase (RNAP) holoenzyme by a catalytic core RNAP and a sigma (σ) initiation factor is essential for bacterial viability. As the primary binding site for the housekeeping σ factors, the RNAP clamp helix domain represents an attractive target for novel antimicrobial agent discovery. Previously, we designed a pharmacophore model based on the essential amino acids of the clamp helix, such as R278, R281, and I291 (Escherichia coli numbering), and identified hit compounds with antimicrobial activity that interfered with the core-σ interactions. In this work, we rationally designed and synthesized a class of triaryl derivatives of one hit compound and succeeded in drastically improving the antimicrobial activity against Streptococcus pneumoniae, with the minimum inhibitory concentration reduced from 256 to 1 μg/mL. Additional characterization of antimicrobial activity, inhibition of transcription, in vitro pharmacological properties, and cytotoxicity of the optimized compounds demonstrated their potential for further development.en_US
dcterms.accessRightsopen accessen_US
dcterms.bibliographicCitationJournal of medicinal chemistry, 23 July 2020, v. 63, no. 14, p. 7695-7720en_US
dcterms.isPartOfJournal of medicinal chemistryen_US
dcterms.issued2020-07-23-
dc.identifier.scopus2-s2.0-85088010039-
dc.identifier.eissn1520-4804en_US
dc.description.validate202103 bcvcen_US
dc.description.oaAccepted Manuscripten_US
dc.identifier.FolderNumbera0615-n02-
dc.identifier.SubFormID601-
dc.description.fundingSourceRGCen_US
dc.description.fundingSourceOthersen_US
dc.description.fundingTextRGC: 25100017, 15100019, C5008-19G||Others: P0009742, P0030472, P000016en_US
dc.description.pubStatusPublisheden_US
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