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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Microbiol. | doi: 10.3389/fmicb.2019.02417

Rewiring of Metabolic network in Mycobacterium tuberculosis during adaptation to different stresses

  • 1Department of Biochemistry, School of Life Sciences, University of Hyderabad, India
  • 2Tata Consultancy Services (India), India
  • 3National Centre for Cell Science, India
  • 4Council of Scientific and Industrial Research (CSIR), India

Abstract
Metabolic adaptation of Mycobacterium tuberculosis (M. tuberculosis) to microbicidal intracellular environment of host macrophages is fundamental to its pathogenicity. However, an in-depth understanding of metabolic adjustments through key reaction pathways and networks is limited. To understand how such changes occur, we measured the cellular metabolome of M. tuberculosis subjected to four microbicidal stresses using liquid chromatography-mass spectrometric multiple reactions monitoring (LC-MRM/MS). Overall, 87 metabolites were identified. The metabolites best describing the separation between stresses were identified through multivariate analysis. The coupling of the metabolite measurements with existing genome-scale metabolic model, and using constraint-based simulation led to several new concepts and unreported observations in M. tuberculosis; such as (i) the high levels of released ammonia as an adaptive response to acidic stress was due to increased flux through L-asparaginase rather than urease activity; (ii) nutrient starvation-induced anaplerotic pathway for generation of TCA intermediates from phosphoenolpyruvate using phosphoenolpyruvate kinase; (iii) quenching of protons through GABA shunt pathway or sugar alcohols as possible mechanisms of early adaptation to acidic and oxidative stresses; and (iv) usage of alternate cofactors by the same enzyme as a possible mechanism of rewiring metabolic pathways to overcome stresses. Besides providing new leads and important nodes that can be used for designing intervention strategies, the study advocates the strength of applying flux balance analyses coupled with metabolomics to get a global picture of complex metabolic adjustments.

Keywords: Metabolic rewiring, Stress adaptation in M. tuberculosis, Genome-scale metabolic network, metabolite profiling, Sugar Alcohols

Received: 12 Jul 2019; Accepted: 07 Oct 2019.

Copyright: © 2019 Rizvi, Shankar, Chatterjee, More, Bose, Dutta, Balakrishnan, Rapole, Mande, Banerjee and Mande. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Sharmila S. Mande, Tata Consultancy Services (India), Pune, India, sharmila.mande@tcs.com
Prof. Sharmistha Banerjee, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Andhra Pradesh, India, sbsl@uohyd.ac.in
Dr. Shekhar C. Mande, Council of Scientific and Industrial Research (CSIR), New Delhi, National Capital Territory of Delhi, India, shekhar@csir.res.in