dc.contributor.author |
Boshoff, HIM |
en |
dc.contributor.author |
Myers, TG |
en |
dc.contributor.author |
Copp, Brent |
en |
dc.contributor.author |
McNeil, MR |
en |
dc.contributor.author |
Wilson, MA |
en |
dc.contributor.author |
Barry, CE |
en |
dc.date.accessioned |
2017-10-29T21:45:02Z |
en |
dc.date.issued |
2004-09-17 |
en |
dc.identifier.citation |
Journal of Biological Chemistry, 279(38):40174-40184, 17 Sep 2004 |
en |
dc.identifier.issn |
0021-9258 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/36273 |
en |
dc.description.abstract |
The differential transcriptional response of Mycobacterium tuberculosis to drugs and growth-inhibitory conditions was monitored to generate a data set of 430 microarray profiles. Unbiased grouping of these profiles independently clustered agents of known mechanism of action accurately and was successful at predicting the mechanism of action of several unknown agents. These predictions were validated biochemically for two agents of previously uncategorized mechanism, pyridoacridones and phenothiazines. Analysis of this data set further revealed 150 underlying clusters of coordinately regulated genes offering the first glimpse at the full metabolic potential of this organism. A signature subset of these gene clusters was sufficient to classify all known agents as to mechanism of action. Transcriptional profiling of both crude and purified natural products can provide critical information on both mechanism and detoxification prior to purification that can be used to guide the drug discovery process. Thus, the transcriptional profile generated by a crude marine natural product recapitulated the mechanistic prediction from the pure active component. The underlying gene clusters further provide fundamental insights into the metabolic response of bacteria to drug-induced stress and provide a rational basis for the selection of critical metabolic targets for screening for new agents with improved activity against this important human pathogen. |
en |
dc.description.uri |
https://www.ncbi.nlm.nih.gov/pubmed/15247240 |
en |
dc.language |
English |
en |
dc.publisher |
American Society for Biochemistry and Molecular Biology |
en |
dc.relation.ispartofseries |
Journal of Biological Chemistry |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.title |
The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism - Novel insights into drug mechanisms of action |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1074/jbc.M406796200 |
en |
pubs.issue |
38 |
en |
pubs.begin-page |
40174 |
en |
pubs.volume |
279 |
en |
dc.rights.holder |
Copyright: American Society for Biochemistry and Molecular Biology |
en |
dc.identifier.pmid |
15247240 |
en |
pubs.author-url |
http://www.jbc.org/content/279/38/40174.long |
en |
pubs.end-page |
40184 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
7475 |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Chemistry |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1083-351X |
en |
pubs.record-created-at-source-date |
2010-09-01 |
en |
pubs.online-publication-date |
2004-07-09 |
en |
pubs.dimensions-id |
15247240 |
en |