File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

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
Keywords4-diphosphocytidyl-2-C-methyl-d-erythritol synthase (CDP-MEP synthase, IspD)
Antituberculosis activity
DMB (Domiphen bromide)
Inhibitor
Target
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
2023 Impact Factor: 4.2
2023 SCImago Journal Rankings: 1.055
ISI Accession Number ID

 

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.subject4-diphosphocytidyl-2-C-methyl-d-erythritol synthase (CDP-MEP synthase, IspD)-
dc.subjectAntituberculosis activity-
dc.subjectDMB (Domiphen bromide)-
dc.subjectInhibitor-
dc.subjectTarget-
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.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.ejphar.2012.08.012-
dc.identifier.pmid22975264-
dc.identifier.scopuseid_2-s2.0-84867336808-
dc.identifier.hkuros266391-
dc.identifier.volume694-
dc.identifier.issue1-3-
dc.identifier.spage45-
dc.identifier.epage52-
dc.identifier.isiWOS:000310177000006-
dc.publisher.placeNetherlands-
dc.identifier.issnl0014-2999-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats