TitleMycobacterium tuberculosis Proteome Response to Antituberculosis Compounds Reveals Metabolic "Escape" Pathways That Prolong Bacterial Survival.
Publication TypeJournal Article
Year of Publication2017
AuthorsDanelishvili, L, Shulzhenko, N, Chinison, JJJ, Babrak, L, Hu, J, Morgun, A, Burrows, G, Bermudez, LE
JournalAntimicrob Agents Chemother
Date Published2017 07
KeywordsAntitubercular Agents, Diarylquinolines, Fluoroquinolones, Isoniazid, Mefloquine, Moxifloxacin, Mycobacterium tuberculosis, Proteome, Proteomics, Rifampin

Tuberculosis (TB) continues to be one of the most common bacterial infectious diseases and is the leading cause of death in many parts of the world. A major limitation of TB therapy is slow killing of the infecting organism, increasing the risk for the development of a tolerance phenotype and drug resistance. Studies indicate that takes several days to be killed upon treatment with lethal concentrations of antibiotics both and To investigate how metabolic remodeling can enable transient bacterial survival during exposure to bactericidal concentrations of compounds, strain H37Rv was exposed to twice the MIC of isoniazid, rifampin, moxifloxacin, mefloquine, or bedaquiline for 24 h, 48 h, 4 days, and 6 days, and the bacterial proteomic response was analyzed using quantitative shotgun mass spectrometry. Numerous sets of bacterial proteins were identified over the 6-day treatment. Network analysis and comparisons between the drug treatment groups revealed several shared sets of predominant proteins and enzymes simultaneously belonging to a number of diverse pathways. Overexpression of some of these proteins in the nonpathogenic extended bacterial survival upon exposure to bactericidal concentrations of antimicrobials, and inactivation of some proteins in prevented the pathogen from escaping the fast killing and in macrophages, as well. Our biology-driven approach identified promising bacterial metabolic pathways and enzymes that might be targeted by novel drugs to reduce the length of tuberculosis therapy.

Alternate JournalAntimicrob Agents Chemother
PubMed ID28416555
PubMed Central IDPMC5487666
Grant ListR01 DK103761 / DK / NIDDK NIH HHS / United States
R21 AI110078 / AI / NIAID NIH HHS / United States