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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 5, 2005; DOI: 10.1124/jpet.105.087817

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Received for publication April 13, 2005.
Revised August 1, 2005.
Accepted for publication August 1, 2005.

Pharmacoproteomic Effects of Isoniazid, Ethambutol and SQ109 on Mycobacterium tuberculosis H37Rv

Lee Jia 1*, Lori Coward 2, Gregory S Gorman 2, Patricia E Noker 2, Joseph E Tomaszewsky 1

1 National Cancer Institute/NIH 2 Southern Research Institute

* Address correspondence to: E-mail: jiale{at}mail.nih.gov

Abstract

The present study was aimed at fingerprinting pharmacoproteomic alterations of the Mycobacterium tuberculosis H37Rv strain induced by antitubercular drugs isoniazid (INH), ethambutol (EMB), and SQ109 (a novel 1,2-diamine-based EMB analog), providing new understanding of pharmacoproteomic mechanisms of each and exploring new drug targets. The three drugs produced significant down-regulation of 13 proteins including immunogenic ModD, Mpt64, with proteins from the PE family being inhibited the most. Alternatively, the three drugs up-regulated 17 proteins including secreted antigenic proteins ESAT-6 and CFP-10. Among these, ESAT-6 and AphC were most effected by INH, while EMB had the greatest effect on ESAT-6. All three drugs produced only moderate up-regulation of aerobic and iron metabolism proteins, i.e., electron transfer flavoprotein Fix A and Fix B, and ferritin-like protein BfrB, suggesting that the interruption of microbacterial energy metabolism is not a primary mechanism of action. INH suppressed ATP-dependent DNA/RNA helicase, but up-regulated {beta}-ketoacyl-acyl carrier protein synthase. These effects may contribute to its bactericidal effects. In contrast, EMB and SQ109 did just the opposite: these drugs up-regulated the helicase and down-regulated the synthase. For most of the H37Rv proteins, similar pharmacoproteomic patterns were found for both EMB and SQ109. None of the drugs significantly regulated expression of chaperonins GroES, GroEL2 and Dnak, suggesting that these drugs do not affect chaperone-mediated nascent polypeptide folding and sorting. The present study identified proteins directly modulated by the actions of INH, EMB and SQ109, and distinguished INH activity from the diamine antitubercular compounds that inhibit M. tuberculosis H37Rv.


Key words: Anti-tuberculosis, Ethambutol, Isoniazid, M. tuberculosis H37Rv, Pharmacoproteomics, SQ109


This article has been cited by other articles:


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B. V. Nikonenko, M. Protopopova, R. Samala, L. Einck, and C. A. Nacy
Drug Therapy of Experimental Tuberculosis (TB): Improved Outcome by Combining SQ109, a New Diamine Antibiotic, with Existing TB Drugs
Antimicrob. Agents Chemother., April 1, 2007; 51(4): 1563 - 1565.
[Abstract] [Full Text] [PDF]


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