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Article: Identification and validation of a novel lead compound targeting 4-diphosphocytidyl-2-C-methylerythritol synthetase (IspD) of mycobacteria

TitleIdentification and validation of a novel lead compound targeting 4-diphosphocytidyl-2-C-methylerythritol synthetase (IspD) of mycobacteria
Authors
Issue Date2012
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejphar
Citation
European Journal of Pharmacology, 2012, v. 694 n. 1-3, p. 45-52 How to Cite?
AbstractTuberculosis is a serious threat to world-wide public health usually caused in humans by Mycobacterium tuberculosis (M. tuberculosis). It exclusively utilizes the methylerythritol phosphate (MEP) pathway for biosynthesis of isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), the precursors of all isoprenoid compounds. The 4-diphosphocytidyl-2-C-methyl-d-erythritol synthase (IspD; EC 2.7.7.60) is the key enzyme of the MEP pathway. It is also of interest as a new chemotherapeutic target, as the enzyme is absent in mammals and ispD is an essential gene for growth. A high-throughput screening method was therefore developed to identify compounds that inhibit IspD. This process was applied to identify a lead compound, domiphen bromide (DMB), that may effectively inhibit IspD. The inhibitory action of DMB was confirmed by over-expressing or down-regulating IspD in Mycobacterium smegmatis (M. smegmatis), demonstrating that DMB inhibit M. smegmatis growth additionally through an IspD-independent pathway. This also led to higher levels of growth inhibition when combined with IspD knockdown. This novel IspD inhibitor was also reported to exhibit antimycobacterial activity in vitro, an effect that likely occurs as a result of perturbation of cell wall biosynthesis.
Persistent Identifierhttp://hdl.handle.net/10722/231187
ISSN
2015 Impact Factor: 2.73
2015 SCImago Journal Rankings: 1.115

 

DC FieldValueLanguage
dc.contributor.authorGao, P-
dc.contributor.authorYang, YH-
dc.contributor.authorXiao, CL-
dc.contributor.authorLiu, YS-
dc.contributor.authorGan, ML-
dc.contributor.authorGuan, Y-
dc.contributor.authorHao, XQ-
dc.contributor.authorMeng, JZ-
dc.contributor.authorZhou, S-
dc.contributor.authorChen, XJ-
dc.date.accessioned2016-09-20T05:21:17Z-
dc.date.available2016-09-20T05:21:17Z-
dc.date.issued2012-
dc.identifier.citationEuropean Journal of Pharmacology, 2012, v. 694 n. 1-3, p. 45-52-
dc.identifier.issn0014-2999-
dc.identifier.urihttp://hdl.handle.net/10722/231187-
dc.description.abstractTuberculosis is a serious threat to world-wide public health usually caused in humans by Mycobacterium tuberculosis (M. tuberculosis). It exclusively utilizes the methylerythritol phosphate (MEP) pathway for biosynthesis of isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), the precursors of all isoprenoid compounds. The 4-diphosphocytidyl-2-C-methyl-d-erythritol synthase (IspD; EC 2.7.7.60) is the key enzyme of the MEP pathway. It is also of interest as a new chemotherapeutic target, as the enzyme is absent in mammals and ispD is an essential gene for growth. A high-throughput screening method was therefore developed to identify compounds that inhibit IspD. This process was applied to identify a lead compound, domiphen bromide (DMB), that may effectively inhibit IspD. The inhibitory action of DMB was confirmed by over-expressing or down-regulating IspD in Mycobacterium smegmatis (M. smegmatis), demonstrating that DMB inhibit M. smegmatis growth additionally through an IspD-independent pathway. This also led to higher levels of growth inhibition when combined with IspD knockdown. This novel IspD inhibitor was also reported to exhibit antimycobacterial activity in vitro, an effect that likely occurs as a result of perturbation of cell wall biosynthesis.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejphar-
dc.relation.ispartofEuropean Journal of Pharmacology-
dc.rightsPosting accepted manuscript (postprint): © <year>. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/-
dc.titleIdentification and validation of a novel lead compound targeting 4-diphosphocytidyl-2-C-methylerythritol synthetase (IspD) of mycobacteria-
dc.typeArticle-
dc.identifier.emailGao, P: gaopeng@hku.hk-
dc.identifier.doi10.1016/j.ejphar.2012.08.012-
dc.identifier.hkuros266391-
dc.identifier.volume694-
dc.identifier.issue1-3-
dc.identifier.spage45-
dc.identifier.epage52-
dc.publisher.placeNetherlands-

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