The Transcriptional Responses of Mycobacterium tuberculosis to Inhibitors of Metabolism
Year: 2004
Type: article
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.
Source: Journal of Biological Chemistry
Authors: Helena I.M. Boshoff, Timothy G. Myers, Brent R. Copp, Michael R. McNeil, Michael A. Wilson, Clifton E. Barry
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funder: National Institutes of Health
Award: G9000232108
OpenAlex ID: W2004361822