De novo histidine biosynthesis protects Mycobacterium tuberculosis from host IFN-γ mediated histidine starvation

Dwivedy, Abhisek; Ashraf, Anam; Jha, Bhavya; Kumar, Deepak; Agarwal, Nisheeth; Biswal, B.K.

doi:10.1038/s42003-021-01926-4

Cited by 28 publications

(26 citation statements)

References 95 publications

(56 reference statements)

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“…Although in this study, DLA has not been established as an exclusive inhibitor for IGPD and its antitubercular activity may be contributed by several other targets, it has shown promising inhibition of Mtb IGPD both biochemically and structurally. Notably, a recent study by our group established that an uninterrupted biosynthesis of histidine is essential for Mtb to evade the host immune response and survive; putting an end to the speculations that Mtb could survive by importing histidine from the host if the pathway is blocked 12 . This new knowledge has significantly enhanced the importance of targeting histidine biosynthesis pathway enzymes.…”

Section: Discussionmentioning

confidence: 98%

“…With the emergence of drug‐resistant Mtb strains, 1,2 TB has resurged as a global emergency, which mandates the need to develop novel therapeutic interventions. Among the vast worldwide efforts in this respect, a plethora of studies showed that the disruption of the function of the individual central metabolic pathways, 3 such as thiamine biosynthesis, 4 amino acid biosynthesis, that is, tryptophan, 5,6 leucine, 7 arginine, 8 serine, 9 histidine, 10‐12 and aspartate biosynthesis, 13 represents new strategies to curb Mtb infection. Mtb , unlike humans, can biosynthesize all amino acids 14 .…”

Section: Introductionmentioning

confidence: 99%

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Characterization of a triazole scaffold compound as an inhibitor of Mycobacterium tuberculosis imidazoleglycerol‐phosphate dehydratase

et al. 2021

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Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), employs ten enzymes including imidazoleglycerol‐phosphate dehydratase (IGPD) for de novo biosynthesis of histidine. The absence of histidine‐biosynthesis in humans combined with its essentiality for Mtb makes the enzymes of this pathway major anti‐TB drug targets. We explored the inhibitory potential of a small molecule β‐(1,2,4‐Triazole‐3‐yl)‐DL‐alanine (DLA) against Mtb IGPD. DLA exhibits an in vitro inhibitory efficacy in the lower micromolar range. Higher‐resolution crystal structures of native and substrate‐bound Mtb IGPD provided additional structural features of this important drug target. Crystal structure of IGPD‐DLA complex at a resolution of 1.75 Å, confirmed that DLA locks down the function of the enzyme by binding in the active site pocket of the IGPD mimicking the substrate‐binding mode to a high degree. In our biochemical study, DLA showed an efficient inhibition of Mtb IGPD. Furthermore, DLA also showed bactericidal activity against Mtb and Mycobacterium smegmatis and inhibited their growth in respective culture medium. Importantly, owing to the favorable ADME and physicochemical properties, it serves as an important lead molecule for further derivatizations.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Characterization of a triazole scaffold compound as an inhibitor of Mycobacterium tuberculosis imidazoleglycerol‐phosphate dehydratase

et al. 2021

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“…The exposure of M. tuberculosis to NSC369066 inhibited its growth in a bactericidal manner and this was partially restored upon supplementation of medium with L-methionine. Similar supplementation studies have been performed to validate enzymes of other amino acid biosynthetic pathways from M. tuberculosis as drug-targets 31 , 35 , 68 – 70 . Although, NSC73735 was inactive against M. tuberculosis , it showed good activity against S. aureus in liquid cultures.…”

Section: Discussionmentioning

confidence: 95%

Identification of small molecules targeting homoserine acetyl transferase from Mycobacterium tuberculosis and Staphylococcus aureus

Chaudhary

Singh

Marzuki

et al. 2022

Sci Rep

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There is an urgent need to validate new drug targets and identify small molecules that possess activity against both drug-resistant and drug-sensitive bacteria. The enzymes belonging to amino acid biosynthesis have been shown to be essential for growth in vitro, in vivo and have not been exploited much for the development of anti-tubercular agents. Here, we have identified small molecule inhibitors targeting homoserine acetyl transferase (HSAT, MetX, Rv3341) from M. tuberculosis. MetX catalyses the first committed step in L-methionine and S-adenosyl methionine biosynthesis resulting in the formation of O-acetyl-homoserine. Using CRISPRi approach, we demonstrate that conditional repression of metX resulted in inhibition of M. tuberculosis growth in vitro. We have determined steady state kinetic parameters for the acetylation of L-homoserine by Rv3341. We show that the recombinant enzyme followed Michaelis–Menten kinetics and utilizes both acetyl-CoA and propionyl-CoA as acyl-donors. High-throughput screening of a 2443 compound library resulted in identification of small molecule inhibitors against MetX enzyme from M. tuberculosis. The identified lead compounds inhibited Rv3341 enzymatic activity in a dose dependent manner and were also active against HSAT homolog from S. aureus. Molecular docking of the identified primary hits predicted residues that are essential for their binding in HSAT homologs from M. tuberculosis and S. aureus. ThermoFluor assay demonstrated direct binding of the identified primary hits with HSAT proteins. Few of the identified small molecules were able to inhibit growth of M. tuberculosis and S. aureus in liquid cultures. Taken together, our findings validated HSAT as an attractive target for development of new broad-spectrum anti-bacterial agents that should be effective against drug-resistant bacteria.

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“…Reduced histidine metabolism has been described in chronic inflammatory disease such as systemic lupus erythematosus ( 30 , 31 , 54 ). IFN-γ has also been demonstrated to upregulate the histidine catabolizing enzymes resulting in the depletion of free histidine ( 55 ). Therefore, the correlations between histidine metabolism and two plasma biomarkers essential for T cell activation emphasized the potential inhibitory effect of histidine metabolism in immune activation and IRIS pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Plasma Metabolomics Reveals Dysregulated Metabolic Signatures in HIV-Associated Immune Reconstitution Inflammatory Syndrome

et al. 2021

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Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory complication associated with an underlying opportunistic infection that can be observed in HIV-infected individuals shortly after the initiation of antiretroviral therapy, despite successful suppression of HIV viral load and CD4+ T cell recovery. Better understanding of IRIS pathogenesis would allow for targeted prevention and therapeutic approaches. In this study, we sought to evaluate the metabolic perturbations in IRIS across longitudinal time points using an unbiased plasma metabolomics approach as well as integrated analyses to include plasma inflammatory biomarker profile and whole blood transcriptome. We found that many lipid and amino acid metabolites differentiated IRIS from non-IRIS conditions prior to antiretroviral therapy and during the IRIS event, implicating the association between oxidative stress, tryptophan pathway, and lipid mediated signaling and the development of IRIS. Lipid and amino acid metabolic pathways also significantly correlated with inflammatory biomarkers such as IL-12p70 and IL-8 at the IRIS event, indicating the role of cellular metabolism on cell type specific immune activation during the IRIS episode and in turn the impact of immune activation on cellular metabolism. In conclusion, we defined the metabolic profile of IRIS and revealed that perturbations in metabolism may predispose HIV-infected individuals to IRIS development and contribute to the inflammatory manifestations during the IRIS event. Furthermore, our findings expanded our current understanding IRIS pathogenesis and highlighted the significance of lipid and amino acid metabolism in inflammatory complications.

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De novo histidine biosynthesis protects Mycobacterium tuberculosis from host IFN-γ mediated histidine starvation

Cited by 28 publications

References 95 publications

Characterization of a triazole scaffold compound as an inhibitor of Mycobacterium tuberculosis imidazoleglycerol‐phosphate dehydratase

Characterization of a triazole scaffold compound as an inhibitor of Mycobacterium tuberculosis imidazoleglycerol‐phosphate dehydratase

Identification of small molecules targeting homoserine acetyl transferase from Mycobacterium tuberculosis and Staphylococcus aureus

Plasma Metabolomics Reveals Dysregulated Metabolic Signatures in HIV-Associated Immune Reconstitution Inflammatory Syndrome

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