Pharmacoproteomic Effects of Isoniazid, Ethambutol, andN-Geranyl-N′-(2-adamantyl)ethane-1,2-diamine (SQ109) onMycobacterium tuberculosisH37Rv
| Autor: | Patricia E. Noker, Lee Jia, Joseph E. Tomaszewski, Gregory S. Gorman, Lori Coward |
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| Rok vydání: | 2005 |
| Předmět: |
Drug
Proteome Protein Hydrolysates media_common.quotation_subject Molecular Sequence Data Antitubercular Agents SQ109 Adamantane Peptide Mapping Chaperonin chemistry.chemical_compound Databases Genetic Isoniazid medicine Trypsin Amino Acid Sequence Ethambutol media_common Pharmacology ATP synthase biology Mycobacterium tuberculosis Ethylenediamines bacterial infections and mycoses RNA Helicase A Peptide Fragments Biochemistry chemistry Mechanism of action Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization biology.protein Molecular Medicine Electrophoresis Polyacrylamide Gel medicine.symptom medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 315:905-911 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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 [N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine, 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 Pro-Glu 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 affected by INH, whereas 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. |
| Databáze: | OpenAIRE |
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