A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis

Gupta, P.; Thomas, S.E.; Zaidan, Shaymaa A.; Pasillas, Maria A.; Cory-Wright, J.; Sebastián-Pérez, Víctor; Burgess, Ailidh; Cattermole, Emma; Meghir, C.; Abell, Chris; Coyne, Anthony G.; Jacobs, William R.; Blundell, Tom L.; Tiwari, Sangeeta; Mendes, V.

doi:10.1016/j.csbj.2021.06.006

Cited by 21 publications

(19 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Preclinical Promisesmentioning

confidence: 99%

“…Ornithine acetyltransferase (ArgJ) is one of eight essential enzymes within the l -arginine biosynthesis pathway, which is critical for Mtb survival . The role of ArgJ is to recycle an acetyl moiety by catalytically transferring this group from N -acetylornithine to the l -glutamate starting material. , In 2018, Mishra and co-workers reported the first inhibitors of Mtb ArgJ . Pranlukast ( 88 ) (Figure ), an asthma medication having widespread use in Japan, was identified as the best hit from a library of approved drugs, following in silico screening and assessment in enzyme assays.…”

Section: Preclinical Promisesmentioning

confidence: 99%

See 1 more Smart Citation

Tuberculosis Drug Discovery: Challenges and New Horizons

et al. 2022

View full text Add to dashboard Cite

Over the past 2000 years, tuberculosis (TB) has claimed more lives than any other infectious disease. In 2020 alone, TB was responsible for 1.5 million deaths worldwide, comparable to the 1.8 million deaths caused by COVID-19. The World Health Organization has stated that new TB drugs must be developed to end this pandemic. After decades of neglect in this field, a renaissance era of TB drug discovery has arrived, in which many novel candidates have entered clinical trials. However, while hundreds of molecules are reported annually as promising anti-TB agents, very few successfully progress to clinical development. In this Perspective, we critically review those anti-TB compounds published in the last 6 years that demonstrate good in vivo efficacy against Mycobacterium tuberculosis. Additionally, we highlight the main challenges and strategies for developing new TB drugs and the current global pipeline of drug candidates in clinical studies to foment fresh research perspectives.

show abstract

Section: Preclinical Promisesmentioning

confidence: 99%

Section: Preclinical Promisesmentioning

confidence: 99%

Tuberculosis Drug Discovery: Challenges and New Horizons

et al. 2022

View full text Add to dashboard Cite

show abstract

“…aerA is the encoding gene of aerolysin, which is a kind of Aeromonas chief toxin [ 19 ]. argF is a key member of the arginine biosynthesis pathway, while the argF deletion mutant of Mycobacterium tuberculosis is rapidly sterilized in mice [ 83 ]. dhaL is associated with glycerol metabolism, which contributes to the cell fitness and virulence of Actinotignum schaalii [ 84 ] and Listeria monocytogenes [ 85 ].…”

Section: Discussionmentioning

confidence: 99%

Enhanced Hemolytic Activity of Mesophilic Aeromonas salmonicida SRW-OG1 Is Brought about by Elevated Temperatures

et al. 2022

View full text Add to dashboard Cite

Aeromonas salmonicida is a well-known cold-water pathogenic bacterium. Previously, we reported the first isolation of pathogenic A. salmonicida from diseased Epinephelus coioides, a kind of warm-water fish, and it was proved to be a putative mesophilic strain with potent pathogenicity to humans. In order to investigate the mechanisms underlying mesophilic growth ability and virulence, the transcriptome of A. salmonicida SRW-OG1 at 18, 28, and 37 °C was analyzed. The transcriptome of A. salmonicida SRW-OG1 at different temperatures showed a clear separation boundary, which might provide valuable information for the temperature adaptation and virulence regulation of A. salmonicida SRW-OG1. Interestingly, aerA and hlyA, the hemolytic genes encoding aerolysin and hemolysin, were found to be significantly up-regulated at 28 and 37 °C. Since aerolysin and hemolysin are the most well-known and -characterized virulence factors of pathogenic Aeromonas strains, the induction of aerA and hlyA was associated with the mesophilic virulence. Further study proved that the extracellular products (ECPs) purchased from A. salmonicida SRW-OG1 cultured at 28 and 37 °C showed elevated hemolytic activity and virulence than those at 18 °C. Moreover, the silence of aerA and hlyA led to significantly decreased hemolysis and virulence. Taken together, our results revealed that the mesophilic virulence of A. salmonicida SRW-OG1 might be due to the enhanced expression of aerA and hlyA induced by elevated temperatures.

show abstract

“…Thus, mutants of argF encoding ornithine carbamoyltransferase exhibit decreased pathogenicity and survival of Mtb in immunocompetent and immunocompromised mice [ 6 ]. Recently, argB mutants have shown decreased survival of Mtb by inducing oxidative stress [ 7 , 8 ]. While all the enzymes of the arginine pathway have been proposed to be essential for Mtb growth, among them argJ has been considered as a promising target for drug discovery and development against Mtb survival due to the lack of a homolog in humans [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, argB mutants have shown decreased survival of Mtb by inducing oxidative stress [ 7 , 8 ]. While all the enzymes of the arginine pathway have been proposed to be essential for Mtb growth, among them argJ has been considered as a promising target for drug discovery and development against Mtb survival due to the lack of a homolog in humans [ 7 , 8 ]. The gene argJ encodes for the monofunctional enzyme ornithine acetyltransferase in Mtb , which acts on the substrates of first and fifth reactions in the arginine biosynthetic pathway [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolite Dysregulation by Pranlukast in Mycobacterium tuberculosis

et al. 2022

View full text Add to dashboard Cite

Mycobacterium tuberculosis has been infecting millions of people worldwide over the years, causing tuberculosis. Drugs targeting distinct cellular mechanisms including synthesis of the cell wall, lipids, proteins, and nucleic acids in Mtb are currently being used for the treatment of TB. Although extensive research is being carried out at the molecular level in the infected host and pathogen, the identification of suitable drug targets and drugs remains under explored. Pranlukast, an allosteric inhibitor of MtArgJ (Mtb ornithine acetyltransferase) has previously been shown to inhibit the survival and virulence of Mtb. The main objective of this study was to identify the altered metabolic pathways and biological processes associated with the differentially expressed metabolites by PRK in Mtb. Here in this study, metabolomics was carried out using an LC-MS/MS-based approach. Collectively, 50 metabolites were identified to be differentially expressed with a significant p-value through a global metabolomic approach using a high-resolution mass spectrometer. Metabolites downstream of argJ were downregulated in the arginine biosynthetic pathway following pranlukast treatment. Predicted human protein interactors of pranlukast-treated Mtb metabolome were identified in association with autophagy, inflammation, DNA repair, and other immune-related processes. Further metabolites including N-acetylglutamate, argininosuccinate, L-arginine, succinate, ergothioneine, and L-phenylalanine were validated by multiple reaction monitoring, a targeted mass spectrometry-based metabolomic approach. This study facilitates the understanding of pranlukast-mediated metabolic changes in Mtb and holds the potential to identify novel therapeutic approaches using metabolic pathways in Mtb.

show abstract

A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis

Abstract: Graphical abstract

Cited by 21 publications

References 42 publications

Tuberculosis Drug Discovery: Challenges and New Horizons

Tuberculosis Drug Discovery: Challenges and New Horizons

Enhanced Hemolytic Activity of Mesophilic Aeromonas salmonicida SRW-OG1 Is Brought about by Elevated Temperatures

Metabolite Dysregulation by Pranlukast in Mycobacterium tuberculosis

Contact Info

Product

Resources

About