Design and Development of <i>Mycobacterium tuberculosis</i> Lysine <i>ɛ</i>‐Aminotransferase Inhibitors for Latent Tuberculosis Infection

Devi, Parthiban Brindha; Saxena, Shalini; Chandran, Manoj; Jonnalagadda, Padma Sridevi; Yadav, Ram Naresh; Srilakshmi, Rudraraju Reshma; Yogeeswari, Perumal; Sriram, Dharmarajan

doi:10.1111/cbdd.12655

Cited by 10 publications

(14 citation statements)

References 11 publications

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“…Diglycolic acid is converted into the corresponding dihydrazide in two steps [21–22] . In a similar fashion as described before, subsequent reaction with N ‐methyl‐ N ‐nitroso‐ N ′‐nitro‐guanidine furnished diacetyloxa‐bis‐ N ‐amino‐nitroguanidine ( 9 ).…”

Section: Resultsmentioning

confidence: 99%

Nitraza‐/Oxa‐Propylene‐ and Hydrazonemethylene‐Bridged 1,2,4‐Nitraminotriazoles and Selected Salts

et al. 2023

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Two new bridged nitraminotriazoles with bridging oxapropylene and nitrazapropylene moieties were synthesized, and converted into several salts, as well as from the hydrazonemethylene bridged nitraminotriazole. All compounds were fully characterized by NMR and IR spectroscopy, elemental analysis as well as differential thermal analysis. The sensitivity towards friction and impact were determined according to BAM standard technics and the energetic properties were calculated by using the EXPLO5 computer code. The neutral compounds as well as the various salts were examined in terms of their physicochemical properties and detonation performance to each other and compared to the commonly used secondary explosive RDX.

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Section: Resultsmentioning

confidence: 99%

Nitraza‐/Oxa‐Propylene‐ and Hydrazonemethylene‐Bridged 1,2,4‐Nitraminotriazoles and Selected Salts

et al. 2023

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“…Altogether, 19 out of 59 proteins exclusively detected in WT, and 38 out of 92 proteins overrepresented in this same strain, have previously been reported to be up-regulated in the proteome of hypoxic bacteria (4, 14, 38, 41, 66, 71–73). This is in very good agreement with reports showing that mycobacteria lacking PknG were unable to grow under hypoxic conditions (50).…”

Section: Discussionmentioning

confidence: 64%

Proteome remodeling in theMycobacterium tuberculosisPknG knockout: molecular evidence for the role of this kinase in cell envelope biogenesis and hypoxia response

Lima

Leyva

Rivera

et al. 2021

Preprint

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Mycobacterium tuberculosis, the ethiological agent of tuberculosis, is among the deadliest human pathogens. One of M. tuberculosis pathogenic hallmarks is its ability to persist in a dormant state in the host for long periods, reinitiating the infectious cycle when favorable environmental conditions are found. Thus, it is not surprising that this pathogen has developed different mechanisms to withstand the stressful conditions found in the host. In particular, the Ser/Thr protein kinase PknG has gained special relevance since it regulates nitrogen metabolism and facilitates bacterial survival inside macrophages. Nevertheless, the molecular mechanisms underlying these effects are far from being elucidated. To further investigate these issues, we performed quantitative proteomics analyses of protein extracts from M. tuberculosis H37Rv and a mutant derivative lacking pknG. Our results showed that in the absence of PknG the mycobacterial proteome was remodeled since 5.7% of the proteins encoded by M. tuberculosis presented significant changes in its relative abundance when compared to the wild-type strain. The main biological processes affected by pknG deletion were the biosynthesis of cell envelope components and the response to hypoxic conditions. As many as 13 DosR-regulated proteins were underrepresented in the pknG deletion mutant, including the distinctive Hrp-1, which was found to be 12-fold decreased according to Parallel Reaction Monitoring experiments. Altogether, the results presented here allow us to postulate that PknG regulation of bacterial adaptation to stress conditions might be an important mechanism underlying its reported effect on intracellular bacterial survival.

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“…Therefore, ppGpp is important for bacterium to persist in an environment that is otherwise not favorable for them, and M. tuberculosis utilizes ppGpp to persist. Parthiban et al (2016) investigated the degradation pathway of lysine on possible enzymes that can be inhibited. In particular, they designed, synthesized, and tested possible inhibitors for LAT.…”

Section: Targets Of the Aspartate Pathwaymentioning

confidence: 99%

The aspartate metabolism pathway

Michael

Sulistyo²

2022

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Recent research has been conducted to find potential new avenues of drug discovery for treating tuberculosis infection. This endless “arms race” is due to the ability of the bacteria to develop resistance towards the already established antibiotic regimen. Various pathways within Mycobacterium tuberculosis are being studied extensively to open new possibilities in drug development. One of which is the aspartate metabolism pathway. This amino acid pathway is proven to be pivotal for the survival of M. tuberculosis both in vitro and in vivo. Furthermore, this pathway also is absent in humans, making it a very promising candidate for further research and development in drug discovery. However, inhibitors against this pathway are not yet available as most suggested inhibitors against the various enzymes within this pathway only made it until the in-silico stage while few studies managed to synthesize their suggested inhibitors and had tested its anti-tuberculosis activity. This review will discuss said attempts in suggesting inhibitors against the critical enzymes that work within this pathway. The inhibitors that are reviewed in this paper are both synthetic and derived from natural products. The multitude of inhibitors proposed and the various enzymes that they are able to inhibit proved that this pathway has potential that is yet to be explored further.

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Design and Development of Mycobacterium tuberculosis Lysine ɛ‐Aminotransferase Inhibitors for Latent Tuberculosis Infection

Cited by 10 publications

References 11 publications

Nitraza‐/Oxa‐Propylene‐ and Hydrazonemethylene‐Bridged 1,2,4‐Nitraminotriazoles and Selected Salts

Nitraza‐/Oxa‐Propylene‐ and Hydrazonemethylene‐Bridged 1,2,4‐Nitraminotriazoles and Selected Salts

Proteome remodeling in theMycobacterium tuberculosisPknG knockout: molecular evidence for the role of this kinase in cell envelope biogenesis and hypoxia response

The aspartate metabolism pathway

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