The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action

The Journal of Biological Chemistry
Helena I M BoshoffClifton E Barry

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...Continue Reading

References

Mar 1, 1992·Trends in Biochemical Sciences·S J ElledgeJ B Allen
Jan 1, 1988·Zentralblatt Für Bakteriologie, Mikrobiologie, Und Hygiene. Series A, Medical Microbiology, Infectious Diseases, Virology, Parasitology·A F YassinG Pulverer
Jan 1, 1980·Methods in Enzymology·L Krivánková, V Dadák
Mar 1, 1995·Antimicrobial Agents and Chemotherapy·L DengM R McNeil
Oct 15, 1996·Proceedings of the National Academy of Sciences of the United States of America·A E BelangerJ M Inamine
Apr 30, 1999·Neuropharmacology·S BalijepalliV Ravindranath
Oct 6, 1999·Current Opinion in Microbiology·K Drlica
Oct 27, 1999·Proceedings of the National Academy of Sciences of the United States of America·M WilsonG K Schoolnik
Feb 3, 2000·Proceedings of the National Academy of Sciences of the United States of America·J J De VossC E Barry
Mar 14, 2000·Current Opinion in Immunology·G Sherlock
Jul 25, 2000·Advances in Microbial Physiology·R K Poole, G M Cook
Jun 21, 2001·Proceedings of the National Academy of Sciences of the United States of America·D R ShermanG K Schoolnik
Oct 10, 2001·Progress in Lipid Research·R J HeathC O Rock
Aug 23, 2002·Journal of Internal Medicine·B Henriques Normark, S Normark
Dec 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·Haiyu ZhangArthur Kornberg
Feb 4, 2003·Nature Medicine·Shahin Rafii, Mihaela Skobe
Feb 18, 2003·Chemical Research in Toxicology·Sandra S MatsumotoLouis R Barrows
Mar 27, 2003·Molecular Microbiology·Christopher M SassettiEric J Rubin
Apr 16, 2003·DNA Research : an International Journal for Rapid Publication of Reports on Genes and Genomes·Christopher J SavoieKosuke Tashiro
Jul 17, 2003·Planta medica·Brent R CoppAlbrecht F Kiderlen
Aug 5, 2003·Proceedings of the National Academy of Sciences of the United States of America·John L DahlClifton E Barry
Sep 4, 2003·The Journal of Experimental Medicine·Dirk SchnappingerGary K Schoolnik
Sep 4, 2003·The Journal of Experimental Medicine·Martin I VoskuilGary K Schoolnik
Sep 13, 2003·The EMBO Journal·Dimitris Brekasis, Mark S B Paget

❮ Previous
Next ❯

Citations

Feb 27, 2010·Applied Microbiology and Biotechnology·Rachel HallerRobert Rutherford
Nov 23, 2006·Biochemistry·Argyrides ArgyrouJohn S Blanchard
Mar 28, 2012·Journal of Medicinal Chemistry·Joy DebnathMichio Kurosu
Dec 20, 2008·Journal of Natural Products·Gemma O'DonnellSimon Gibbons
Jan 8, 2013·Nature Biotechnology·Mark P BrynildsenJames J Collins
Mar 23, 2010·Nature Chemical Biology·Rainer KalscheuerWilliam R Jacobs
Mar 8, 2007·Nature Medicine·Gyanu Lamichhane, William Bishai
Jul 30, 2005·Nature Reviews. Drug Discovery·Markus R Wenk
Dec 21, 2004·Nature Reviews. Microbiology·Helena I M Boshoff, Clifton E Barry
Dec 15, 2007·Nature Reviews. Microbiology·James C SacchettiniJoel S Freundlich
Oct 27, 2009·Nature Reviews. Microbiology·Clifton E BarryDouglas Young
Dec 18, 2010·Nature Reviews. Microbiology·Julian G HurdleRichard E Lee
May 2, 2006·Nature Structural & Molecular Biology·Argyrides ArgyrouJohn S Blanchard
Oct 23, 2009·Proceedings of the National Academy of Sciences of the United States of America·M Sloan SiegristEric J Rubin
Sep 30, 2010·Proceedings of the National Academy of Sciences of the United States of America·Sriram Chandrasekaran, Nathan D Price
Sep 8, 2011·Proceedings of the National Academy of Sciences of the United States of America·Adam J WolpawBrent R Stockwell
Apr 5, 2012·Proceedings of the National Academy of Sciences of the United States of America·Amy K BarczakDeborah T Hung
Jun 27, 2013·Proceedings of the National Academy of Sciences of the United States of America·Sarah A StanleyDeborah T Hung
Jun 19, 2013·Proceedings of the National Academy of Sciences of the United States of America·Feng WangPeter G Schultz
Nov 10, 2011·The Journal of Biological Chemistry·Ján BurianCharles J Thompson
Jun 9, 2005·The Journal of Experimental Medicine·Stefan H E KaufmannCarl Nathan
Aug 13, 2010·The Journal of Infectious Diseases·Smriti MehraDeepak Kaushal
Mar 4, 2008·Journal of Computational Biology : a Journal of Computational Molecular Cell Biology·Jutta GebertRainer Schrader
Apr 21, 2005·Bioinformatics·Lawrence CabusoraChristian V Forst
Dec 26, 2008·The Journal of Antimicrobial Chemotherapy·Richard A Slayden, John T Belisle
Sep 21, 2011·The Journal of Antimicrobial Chemotherapy·Tina Wecke, Thorsten Mascher
Dec 12, 2012·The Journal of Antimicrobial Chemotherapy·Ashley J WarmanGiancarlo A Biagini
Oct 9, 2013·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Rupam BiswasAmit Kumar Das
Dec 7, 2013·Science Translational Medicine·Srinivasa P S RaoUjjini H Manjunatha
Jul 13, 2011·Antimicrobial Agents and Chemotherapy·Ellen G ChristensenVicky G Kastbjerg
Jul 1, 2009·Antimicrobial Agents and Chemotherapy·Santiago Ramón-GarcíaJosé A Aínsa
Jan 22, 2013·Antimicrobial Agents and Chemotherapy·Jansy SarathyMartin Gengenbacher
Feb 27, 2013·Antimicrobial Agents and Chemotherapy·Lucile PinaultDonald R Ronning
Oct 28, 2005·Antimicrobial Agents and Chemotherapy·Zhifang XieEric J Rubin
Jun 15, 2007·Applied and Environmental Microbiology·Clemente I MonteroRobert M Kelly
Jun 7, 2011·Applied and Environmental Microbiology·Paul CarrollTanya Parish

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antitubercular Agents (ASM)

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Antitubercular Agents

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.