Mycobacterium tuberculosis proteome response to anti-tuberculosis compounds reveals metabolic "escape" pathways that prolong bacterial survival [PublishAheadOfPrint]

Tuberculosis (TB) continues to be one of the most common bacterial infectious diseases and the leading cause of death in many parts of the world. A major limitation of TB therapy is slow killing of infecting organism, increasing the risk for the development of tolerance phenotype and drug-resistance. Studies indicate that M. tuberculosis (Mtb) takes several days to be killed upon treatment with lethal concentrations of antibiotics both in vitro and in vivo. To investigate how metabolic remodeling can enable transient bacterial survival during exposure with bactericidal concentrations of compounds, Mtb H37Rv strain was exposed to twice of the minimal inhibitory concentration of isoniazid, rifampicin, moxifloxacin, mefloquine or bedaquiline for 24h, 48h, 4 days, and 6 days, and the bacterial proteomic response was analyzed using the quantitative shotgun mass spectrometry. Numerous sets of de novo bacterial proteins were identified over six-day treatment. Networking analysis and comparisons between each 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 non-pathogenic M. smegmatis extended bacterial survival upon exposure to bactericidal concentrations of antimicrobials, and inactivation of some proteins in Mtb prevented the pathogen from escaping the fast killing in vitro 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.

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