Isocitrate lyase encoding plasmids in BCG cause increased survival in ApoB100-only LDLR−/− mice

Szabó, Ágnes; Endrész, Valéria; Somogyvári, Ferenc; Miczák, András; Faludi, Ildiko

doi:10.1007/s11033-013-2568-5

Cited by 1 publication

(1 citation statement)

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“…4 ). This is partly supported from a previous finding in that recombinant BCG expressing more copies of icl1 had a higher survival rate in infected mice 66 . Recently, Mtb has shown to have an alternate route to mitigate the propionate toxicity; the biosynthesis of PDIM (phthiocerol dimycocerocates) through the drainage of toxic intermediates of the propionate metabolism 36 .…”

Section: Discussionsupporting

confidence: 82%

Glutamate mediated metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis

Lee

Lim

Gao

et al. 2018

Sci Rep

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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.

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Section: Discussionsupporting

confidence: 82%