The Mur Enzymes Chink in the Armour of Mycobacterium tuberculosis cell wall

Shinde, Yashodeep; Ahmad, Iqrar; Surana, Sanjay J.; Patel, Harun

doi:10.1016/j.ejmech.2021.113568

Cited by 18 publications

(10 citation statements)

References 66 publications

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“…Evaluation of targets of 31 existing drugs or investigational compounds (36 genes) ( Table S5 ) were predominantly suppressed in mice (19 down-regulated and 3 upregulated) and in vitro (26 down-regulated and 2 upregulated). Notable exceptions to downregulation of drug targets were increased expression of the genes for Mur ligases B and C that initiate peptidoglycan synthesis in mice 65 and increased expression of rfe, the gene for phosphoglycosyltransferases WecA that initiates arabinogalactan synthesis in mice and in vitro. 66…”

Section: Resultsmentioning

confidence: 99%

Transcriptional adaptation of drug-tolerantMycobacterium tuberculosisin mice

Wynn

Dide-Agossou²,

Reichlen

et al. 2023

Preprint

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Transcriptome evaluation ofMycobacterium tuberculosisin the lungs of laboratory animals during long-term treatment has been limited by extremely low abundance of bacterial mRNA relative to eukaryotic RNA. Here we report a targeted amplification RNA sequencing method called SEARCH-TB. After confirming that SEARCH-TB recapitulates conventional RNA-seqin vitro, we applied SEARCH-TB toMycobacterium tuberculosis-infected BALB/c mice treated for up to 28 days with the global standard isoniazid, rifampin, pyrazinamide, and ethambutol regimen. We compared results in mice with 8-day exposure to the same regimenin vitro. After treatment of mice for 28 days, SEARCH-TB suggested broad suppression of genes associated with bacterial growth, transcription, translation, synthesis of rRNA proteins and immunogenic secretory peptides. Adaptation of drug-stressedMycobacterium tuberculosisappeared to include a metabolic transition from ATP-maximizing respiration towards lower-efficiency pathways, modification and recycling of cell wall components, large-scale regulatory reprogramming, and reconfiguration of efflux pumps expression. Despite markedly different expression at pre-treatment baseline, murine andin vitrosamples had broadly similar transcriptional change during treatment. The differences observed likely indicate the importance of immunity and pharmacokinetics in the mouse. By elucidating the long-term effect of tuberculosis treatment on bacterial cellular processesin vivo, SEARCH-TB represents a highly granular pharmacodynamic monitoring tool with potential to enhance evaluation of new regimens and thereby accelerate progress towards a new generation of more effective tuberculosis treatment.

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Section: Resultsmentioning

confidence: 99%

Transcriptional adaptation of drug-tolerantMycobacterium tuberculosisin mice

Wynn

Dide-Agossou²,

Reichlen

et al. 2023

Preprint

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“…The whole Mur enzymes are crucial for cell integrity and unique to prokaryotes that make these enzymes the most promising target to develop a new drug. 51 , 52 In Gram-negative bacteria, fosfomycin inhibits the MurA enzyme, but mycobacterial MurA has no active site for fosfomycin attachment. Fosfomycin analogs that can inhibit MTB MurA are the most promising to develop a new drug.…”

Section: Pg Synthesis Inhibitormentioning

confidence: 99%

Recent Progress in the Development of Novel Mycobacterium Cell Wall Inhibitor to Combat Drug-Resistant Tuberculosis

Belete

2022

Microbiol�Insights

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Despite decades of research in drug development against TB, it is still the leading cause of death due to infectious diseases. The long treatment duration, patient noncompliance coupled with the ability of the tuberculosis bacilli to resist the current drugs increases multidrug-resistant tuberculosis that exacerbates the situation. Identification of novel drug targets is important for the advancement of drug development against Mycobacterium tuberculosis. The development of an effective treatment course that could help us eradicates TB. Hence, we require drugs that could eliminate the bacteria and shorten the treatment duration. This review briefly describes the available data on the peptidoglycan component structural characterization, identification of the metabolic pathway, and the key enzymes involved in the peptidoglycan synthesis, like N-Acetylglucosamine-1-phosphate uridyltransferase, mur enzyme, alanine racemase as well as their inhibition. Besides, this paper also provides studies on mycolic acid and arabinogalactan synthesis and the transport mechanisms that show considerable promise as new targets to develop a new product with their inhibiter.

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“…Globally, the TB rate is declining at a rate of about 2% per year, and it declined by 11% between 2015 and 2020. 1 − 3 …”

Section: Introductionmentioning

confidence: 99%

“…TB is the 13th leading cause of mortality worldwide and the second leading infectious killer after COVID-19 (above HIV/acquired immunodeficiency syndrome (AIDS)). In 2020, there are estimated 10 million new cases of tuberculosis (TB) worldwide, including 3.3 million women, 5.6 million men, and 1.1 million children. − The 30 most high-burden countries in 2020 will account for 86% of new TB cases. Eight countries make up two-thirds of the total, with India leading the pack, followed by China, Indonesia, the Philippines, Pakistan, Nigeria, Bangladesh, and South Africa.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Molecular Modeling Study, and Quantum-Chemical-Based Investigations of Isoindoline-1,3-diones as Antimycobacterial Agents

et al. 2022

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The condensation of phthalic anhydride afforded structurally modified isoindoline-1,3-dione derivatives with selected amino-containing compounds. The title compounds ( 2 – 30 ) have been characterized by thin-layer chromatography (TLC), infrared spectroscopy, 1 H and 13 C NMR spectroscopy, and mass spectroscopy. All of the compounds were assessed for their antimycobacterial activity toward the H37Rv strain by a dual read-out assay method. Among the synthesized compounds, compound 27 possessed a significant IC 50 of 18 μM, making it the most potent compound of the series. The InhA inhibitory (IC 50 ) activity of compound 27 was 8.65 μM in comparison to Triclosan (1.32 μM). Computational studies like density functional theory (DFT) study, molecular docking, and dynamic simulation studies illustrated the reactivity and stability of the synthesized compounds as InhA inhibitors. A quantum-mechanics-based DFT study was carried out to investigate the molecular and electronic properties, reactivities, and nature of bonding present in the synthesized compounds and theoretical vibrational (IR) and isotropic value ( 1 H and 13 C NMR) calculations.

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The Mur Enzymes Chink in the Armour of Mycobacterium tuberculosis cell wall

Cited by 18 publications

References 66 publications

Transcriptional adaptation of drug-tolerantMycobacterium tuberculosisin mice

Transcriptional adaptation of drug-tolerantMycobacterium tuberculosisin mice

Recent Progress in the Development of Novel Mycobacterium Cell Wall Inhibitor to Combat Drug-Resistant Tuberculosis

Synthesis, Molecular Modeling Study, and Quantum-Chemical-Based Investigations of Isoindoline-1,3-diones as Antimycobacterial Agents

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