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J. Biol. Chem., Vol. 279, Issue 38, 40174-40184, September 17, 2004

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The Transcriptional Responses of Mycobacterium tuberculosis to Inhibitors of Metabolism

NOVEL INSIGHTS INTO DRUG MECHANISMS OF ACTION^*

Helena I. M. Boshoff, Timothy G. Myers¶, Brent R. Copp||, Michael R. McNeil**, Michael A. Wilson¶, and Clifton E. Barry, III

From the Tuberculosis Research Section, NIAID, National Institutes of Health, Rockville, Maryland 20852, the ^¶Research Technologies Branch, NIAID, National Institutes of Health, Bethesda, Maryland 20892, the ^||Department of Chemistry, University of Auckland, Auckland 1020, New Zealand, and the ^**Department of Microbiology, Colorado State University, Ft. Collins, Colorado 80523

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.

Received for publication, June 17, 2004 , and in revised form, July 9, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

To whom correspondence should be addressed: Twinbrook II, Rm. 239, 12441 Parklawn Dr., Rockville, MD 20852. Tel.: 301-4519438; Fax: 301-4020993; E-mail: HBOSHOFF{at}niaid.nih.gov.

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