The proteomic response of Mycobacterium smegmatis to anti-tuberculosis drugs suggests targeted pathways.
Mycobacterium smegmatis is a fast-growing model mycobacterial system that shares many features with the pathogenic Mycobacterium tuberculosis while allowing practical proteomics analysis. With the use of shotgun-style mass spectrometry, we provide a large-scale analysis of the M. smegmatis proteomic response to the anti-tuberculosis (TB) drugs isoniazid, ethambutol, and 5-chloropyrazinamide and elucidate the drugs' systematic effects on mycobacterial proteins. A total of 2550 proteins were identified with approximately 5% false-positive identification rate across 60 experiments, representing approximately 40% of the M. smegmatis proteome ( approximately 6500 proteins). Protein differential expression levels were estimated from the shotgun proteomics data, and 485 proteins showing altered expression levels in response to drugs were identified at a 99% confidence level. Proteomic comparison of anti-TB drug responses shows that translation, cell cycle control, and energy production are down-regulated in all three drug treatments. In contrast, systems related to the drugs' targets, such as lipid, amino acid, and nucleotide metabolism, show specific protein expression changes associated with a particular drug treatment. We identify proteins involved in target pathways for the three drugs and infer putative targets for 5-chloropyrazinamide.
Wang
Rong
R
Center for Systems and Synthetic Biology, Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
Marcotte
Edward M
EM
D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D013058:Mass Spectrometry; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D040901:Proteomics
D000995:Antitubercular Agents; D001426:Bacterial Proteins