Intracellular Mycobacterium tuberculosis Exploits Multiple Host Nitrogen Sources during Growth in Human Macrophages

Borah, Khushboo; Beyß, Martin; Theorell, Axel; Wu, Huihai; Basu, Piyali; Mendum, Tom A.; Nöh, Katharina; Beste, Dany J. V.; McFadden, Johnjoe

doi:10.1016/j.celrep.2019.11.037

Cited by 69 publications

(102 citation statements)

References 79 publications

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“…Mutation in phosphoserine aminotransaminase, serC that converts pyruvate to serine has shown that serC is required for growth of bacteria in serine auxotrophy. Further, similar results were observed in Mtb THP‐1 macrophages where, growth of serC mutant was tremendously impaired compared to wild type and serine complemented bacteria 74 …”

Section: Enzymes Of Amino Acid Metabolism As Drug Targetssupporting

confidence: 77%

Targeting amino acid metabolism of Mycobacterium tuberculosis for developing inhibitors to curtail its survival

Yelamanchi

Surolia

2021

IUBMB Life

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Tuberculosis caused by the bacterium, Mycobacterium tuberculosis (Mtb), continues to remain one of the most devastating infectious diseases afflicting humans. Although there are several drugs for treating tuberculosis available currently, the emergence of the drug resistant forms of this pathogen has made its treatment and eradication a challenging task. While the replication machinery, protein synthesis and cell wall biogenesis of Mtb have been targeted often for anti-tubercular drug development a number of essential metabolic pathways crucial to its survival have received relatively less attention. In this context a number of amino acid biosynthesis pathways have recently been shown to be essential for the survival and pathogenesis of Mtb. Many of these pathways and or their key enzymes homologs are absent in humans hence they could be harnessed for anti-tubercular drug development. In this review, we describe comprehensively the amino acid metabolic pathways essential in Mtb and the key enzymes involved therein that are being investigated for developing inhibitors that compromise the survival and pathogenesis caused by this pathogen.

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Section: Enzymes Of Amino Acid Metabolism As Drug Targetssupporting

confidence: 77%

Targeting amino acid metabolism of Mycobacterium tuberculosis for developing inhibitors to curtail its survival

Yelamanchi

Surolia

2021

IUBMB Life

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“…Mtb is known to be able to acquire and assimilate multiple carbon sources from the host during infection (5, 6, 13, 19). This co-catabolism has been demonstrated to occur both in vitro and during intracellular growth (14).…”

Section: Discussionmentioning

confidence: 99%

“…Within a subset of these, isotopologue abundances for the fragment formed by cleavage of the C2–C3 bond in serine were also determined allowing comprehensive characterization of the isotopic incorporation into serine. Mass spectra of the derivatized amino acids were corrected for the natural abundance of all stable isotopes (4, 6).…”

Section: Methodsmentioning

confidence: 99%

Metabolic flux partitioning between the TCA cycle and glyoxylate shunt combined with a reversible methyl citrate cycle provide nutritional flexibility forMycobacterium tuberculosis

Borah

et al. 2021

Preprint

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The utilisation of multiple host-derived carbon substrates is required by Mycobacterium tuberculosis (Mtb) to successfully sustain a tuberculosis infection thereby identifying the Mtb specific metabolic pathways and enzymes required for carbon co-metabolism as potential drug targets. Metabolic flux represents the final integrative outcome of many different levels of cellular regulation that contribute to the flow of metabolites through the metabolic network. It is therefore critical that we have an in-depth understanding of the rewiring of metabolic fluxes in different conditions. Here, we employed 13C-metabolic flux analysis using stable isotope tracers (13C and 2H) and lipid fingerprinting to investigate the metabolic network of Mtb growing slowly on physiologically relevant carbon sources in a steady state chemostat. We demonstrate that Mtb is able to efficiently co-metabolise combinations of either cholesterol or glycerol along with C2 generating carbon substrates. The uniform assimilation of the carbon sources by Mtb throughout the network indicated no compartmentalization of metabolism in these conditions however there were substrate specific differences in metabolic fluxes. This work identified that partitioning of flux between the TCA cycle and the glyoxylate shunt combined with a reversible methyl citrate cycle as the critical metabolic nodes which underlie the nutritional flexibility of Mtb. These findings provide new insights into the metabolic architecture that affords adaptability of Mtb to divergent carbon substrates.ImportanceEach year more than 1 million people die of tuberculosis (TB). Many more are infected but successfully diagnosed and treated with antibiotics, however antibiotic-resistant TB isolates are becoming ever more prevalent and so novel therapies are urgently needed that can effectively kill the causative agent. Mtb specific metabolic pathways have been identified as an important drug target in TB. However the apparent metabolic plasticity of this pathogen presents a major obstacle to efficient targeting of Mtb specific vulnerabilities and therefore it is critical to define the metabolic fluxes that Mtb utilises in different conditions. Here, we used 13C-metabolic flux analysis to measure the metabolic fluxes that Mtb uses whilst growing on potential in vivo nutrients. Our analysis identified selective use of the metabolic network that included the TCA cycle, glyoxylate shunt and methyl citrate cycle. The metabolic flux phenotypes determined in this study improves our understanding about the co-metabolism of multiple carbon substrates by Mtb identifying a reversible methyl citrate cycle and the glyoxylate shunt as the critical metabolic nodes which underlie the nutritional flexibility of Mtb.

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“…The authors also suggested that greater emphasis should be placed on amino acids as sole carbon sources to better mimic physiologically relevant conditions found in the host. Borah et al used 15 N-flux spectral ratio analysis to demonstrate that M.tb in macrophages has access to multiple amino acids for nitrogen metabolism and identified serine as an amino acid not available to intracellular bacilli [95]. The proteinogenic amino acid serine that provides the nitrogen backbone for glycine and cysteine synthesis must be synthesized by intracellular M.tb, highlighting this pathway, and phosphoserine transaminase in particular, as a novel target for drug discovery.…”

Section: Target Identificationmentioning

confidence: 99%

Multi-Omics Technologies Applied to Tuberculosis Drug Discovery

et al. 2020

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Multi-omics strategies are indispensable tools in the search for new anti-tuberculosis drugs. Omics methodologies, where the ensemble of a class of biological molecules are measured and evaluated together, enable drug discovery programs to answer two fundamental questions. Firstly, in a discovery biology approach, to find new targets in druggable pathways for target-based investigation, advancing from target to lead compound. Secondly, in a discovery chemistry approach, to identify the mode of action of lead compounds derived from high-throughput screens, progressing from compound to target. The advantage of multi-omics methodologies in both of these settings is that omics approaches are unsupervised and unbiased to a priori hypotheses, making omics useful tools to confirm drug action, reveal new insights into compound activity, and discover new avenues for inquiry. This review summarizes the application of Mycobacterium tuberculosis omics technologies to the early stages of tuberculosis antimicrobial drug discovery.

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Intracellular Mycobacterium tuberculosis Exploits Multiple Host Nitrogen Sources during Growth in Human Macrophages

Cited by 69 publications

References 79 publications

Targeting amino acid metabolism of Mycobacterium tuberculosis for developing inhibitors to curtail its survival

Targeting amino acid metabolism of Mycobacterium tuberculosis for developing inhibitors to curtail its survival

Metabolic flux partitioning between the TCA cycle and glyoxylate shunt combined with a reversible methyl citrate cycle provide nutritional flexibility forMycobacterium tuberculosis

Multi-Omics Technologies Applied to Tuberculosis Drug Discovery

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