Metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis

Lee, Jae Jin, Lim, Juhyeon, Gao, Shengjia , Lawson, Christopher, Odell, Mark, Raheem, Saki, Woo, JeongIm, Kang, Sung-Ho, Jeon, Bo-Young and Eoh, Hyungjin (2018) Metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis. Scientific Reports, 8 (8506). pp. 1-13. ISSN 2045-2322

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Metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis
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Metabolic networks in biological systems are interconnected, such that malfunctioning parts can be corrected by other parts within the network, a process termed adaptive metabolism. Unlike Bacillus Calmette-Guérin (BCG), Mycobacterium tuberculosis (Mtb) better manages its intracellular lifestyle by executing adaptive metabolism. Here, we used metabolomics and identified glutamate synthase (GltB/D) that converts glutamine to glutamate (Q → E) as a metabolic effort used to neutralize cytoplasmic pH that is acidified while consuming host propionate carbon through the methylcitrate cycle (MCC). Methylisocitrate lyase, the last step of the MCC, is intrinsically downregulated in BCG, leading to obstruction of carbon flux toward central carbon metabolism, accumulation of MCC intermediates, and interference with GltB/D mediated neutralizing activity against propionate toxicity. Indeed, vitamin B12 mediated bypass MCC and additional supplement of glutamate led to selectively correct the phenotypic attenuation in BCG and restore the adaptive capacity of BCG to the similar level of Mtb phenotype. Collectively, a defective crosstalk between MCC and Q → E contributes to attenuation of intracellular BCG. Furthermore, GltB/D inhibition enhances the level of propionate toxicity in Mtb. Thus, these findings revealed a new adaptive metabolism and propose GltB/D as a synergistic target to improve the antimicrobial outcomes of MCC inhibition in Mtb.

Keywords:Mycobacterium tuberculosis, metabolic profiling, metabolic neutralisation, intracellular growth
Subjects:C Biological Sciences > C530 Bacteriology
C Biological Sciences > C521 Medical Microbiology
C Biological Sciences > C730 Metabolic Biochemistry
C Biological Sciences > C510 Applied Microbiology
C Biological Sciences > C500 Microbiology
Divisions:College of Science > School of Life Sciences
ID Code:39025
Deposited On:02 Dec 2019 10:10

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