Insight into novel clinical mutants of RpsA-S324F, E325K, and G341R of Mycobacterium tuberculosis associated with pyrazinamide resistance

Khan, Muhammad Tahir; Rehaman, Ashfaq Ur; Junaid, Muhammad; Malik, Shaukat Iqbal; Wei, Dong‐Qing

doi:10.1016/j.csbj.2018.09.004

Cited by 32 publications

(18 citation statements)

References 50 publications

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“…Additionally, the distance count profile was plotted to show the stability behavior of all the ligand-bound complexes. This graph supports our distance analysis among the protein and ligand, that the PPRAδ-oleanolic acid complex attained stable behaviors but other two compounds concerning time attained various behaviors which further indicates the less potency, that regarding MD simulation time these two-compound attained various pattern of interaction, in-out behavior which is inappropriate for the high potency of the corresponding compounds [34][35][36][37][38]. The proteinligand (PL) interaction for PPRAδ-Lauric acid, PPRAδ-Oleanolic acid, and PPRAδ-bis(2-ethylhexyl) phthalate profiles were depicted in Fig 7.…”

Section: Inspection Of Stability Of the Bound And Unbound Ligand Compsupporting

confidence: 82%

Bioactive Compounds from <em>Monotheca Buxifolia</em> Inhibit the Growth of Hepatocellular Carcinoma Cells

Hassan¹,

Rehman²,

Jamal³

et al. 2020

Preprint

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The natural products and conventional chemotherapeutic drugs are believed to increase the cure rates of anti-cancer treatment while reducing their toxicity. The current study investigates the cytotoxic and apoptogenic effects of bioactive compounds from Monotheca buxifolia on Hep G2 cell lines. The effect on the viability of Hep G2 cells was evaluated by MTT assay; Morphological changes were studied, the apoptotic activity was demonstrated through Annexin-V-FITC/ PI, a molecular dynamics simulation study was conducted to explore the binding pattern of the compounds in the active site of the PPRAδ protein. The isolated compounds lauric acid, oleanolic acid, and bis(2-ethylhexyl) phthalate inhibited the growth of hepatocellular cancer cells, as determined by MTT assay and annexin V-FITC/PI. The IC50 value for lauric acid was 56.4584 ± 1.20 µg/ml, that for oleanolic acid was 31.9421 ± 1.03 µg/ml, and that for bis(2-ethylhexyl) phthalate was 83.8019 ± 2.18 µg/ml. After 24 h of treatment, 29.5% of Hep G2 cells treated with lauric acid, 52.1% of those treated with oleanolic acid, and 22.4% of those treated with bis(2-ethylhexyl) phthalate were apoptotic. Morphological assay and Hoechst staining microscopy revealed the morphological alterations of cell membrane accompanied by nuclear condensation after treatment. The high fluctuation indicates the high potency and adopting various interactions, and vice versa, the oleanolic acid showed highly residues fluctuation, which remains stable in the active site of PPARδ protein and involved in various interactions while remaining locally fluctuated in the binding site the other two compounds. In conclusion, a significant apoptogenic effect was exhibited by lauric acid, oleanolic acid, and bis(2-ethylhexyl) phthalate against HepG2 cells in inducing apoptosis. Our findings indicate that these bioactive compounds hold promise as potential therapeutic for hepatocellular carcinoma.

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Section: Inspection Of Stability Of the Bound And Unbound Ligand Compsupporting

confidence: 82%

Bioactive Compounds from <em>Monotheca Buxifolia</em> Inhibit the Growth of Hepatocellular Carcinoma Cells

Hassan¹,

Rehman²,

Jamal³

et al. 2020

Preprint

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“…Inhibited protein formation has also been suggested in a proteomics study of Mtb treated with ciprofloxacin [135], as well as a metabolomics study of M. smegmatis treated with ciprofloxacin [48]. Disruption of protein synthesis has also been reported in studies investigating the response of Mtb to pretomanid, streptomycin, EMB, RIF, PZA, and INH [95,[136][137][138]. The inhibited protein synthesis observed would in turn disrupt the functionality of membrane proteins, subsequently inhibiting nutrient uptake as well as fatty acid transport to the cell wall [42].…”

Section: Discussionmentioning

confidence: 88%

Elucidating the Antimycobacterial Mechanism of Action of Ciprofloxacin Using Metabolomics

et al. 2021

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In the interest of developing more effective and safer anti-tuberculosis drugs, we used a GCxGC-TOF-MS metabolomics research approach to investigate and compare the metabolic profiles of Mtb in the presence and absence of ciprofloxacin. The metabolites that best describe the differences between the compared groups were identified as markers characterizing the changes induced by ciprofloxacin. Malic acid was ranked as the most significantly altered metabolite marker induced by ciprofloxacin, indicative of an inhibition of the tricarboxylic acid (TCA) and glyoxylate cycle of Mtb. The altered fatty acid, myo-inositol, and triacylglycerol metabolism seen in this group supports previous observations of ciprofloxacin action on the Mtb cell wall. Furthermore, the altered pentose phosphate intermediates, glycerol metabolism markers, glucose accumulation, as well as the reduction in the glucogenic amino acids specifically, indicate a flux toward DNA (as well as cell wall) repair, also supporting previous findings of DNA damage caused by ciprofloxacin. This study further provides insights useful for designing network whole-system strategies for the identification of possible modes of action of various drugs and possibly adaptations by Mtb resulting in resistance.

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“…Mutants were generated at positions S324F, E325K, G341R, D342N, D343N, A344P, I351F, T370P, and W403G using PYMOL (DeLano, 2002). Free energy differences between MTs and WT RpsA from our previous papers (Khan et al, 2018c(Khan et al, , 2019bRehman et al, 2019) were re-analyzed. PZA is a prodrug, activated by MTB encoded pncA into POA, targeting RpsA.…”

Section: Mutants Selection In Rpsamentioning

confidence: 99%

Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance

Khan

Ali

Zeb³

et al. 2020

Front. Mol. Biosci.

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A central approach for better understanding the forces involved in maintaining protein structures is to investigate the protein folding and thermodynamic properties. The effect of the folding process is often disturbed in mutated states. To explore the dynamic properties behind mutations, molecular dynamic (MD) simulations have been widely performed, especially in unveiling the mechanism of drug failure behind mutation. When comparing wild type (WT) and mutants (MTs), the structural changes along with solvation free energy (SFE), and Gibbs free energy (GFE) are calculated after the MD simulation, to measure the effect of mutations on protein structure. Pyrazinamide (PZA) is one of the first-line drugs, effective against latent Mycobacterium tuberculosis isolates, affecting the global TB control program 2030. Resistance to this drug emerges due to mutations in pncA and rpsA genes, encoding pyrazinamidase (PZase) and ribosomal protein S1 (RpsA) respectively. The question of how the GFE may be a measure of PZase and RpsA stabilities, has been addressed in the current review. The GFE and SFE of MTs have been compared with WT, which were already found to be PZA-resistant. WT structures attained a more stable state in comparison with MTs. The physiological effect of a mutation in PZase and RpsA may be due to the difference in energies. This difference between WT and MTs, depicted through GFE plots, might be useful in predicting the stability and PZA-resistance behind mutation. This study provides useful information for better management of drug resistance, to control the global TB problem.

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Insight into novel clinical mutants of RpsA-S324F, E325K, and G341R of Mycobacterium tuberculosis associated with pyrazinamide resistance

Cited by 32 publications

References 50 publications

Bioactive Compounds from <em>Monotheca Buxifolia</em> Inhibit the Growth of Hepatocellular Carcinoma Cells

Bioactive Compounds from <em>Monotheca Buxifolia</em> Inhibit the Growth of Hepatocellular Carcinoma Cells

Elucidating the Antimycobacterial Mechanism of Action of Ciprofloxacin Using Metabolomics

Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance

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