Enhance the Antimycobacterial Activity of Streptomycin with Ebselen as an Antibiotic Adjuvant Through Disrupting Redox Homeostasis

Drug Design Development and Therapy, Journal Year: 2024, Volume and Issue: Volume 18, P. 3811 - 3824

Published: Aug. 1, 2024

Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes reduction global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) causes an imbalance in redox status bacteria. Previous work has shown that synergistic action bTrxR sensitization to common antibiotics by EbSe is promising strategy for treatment DR pathogens. Thus, we aimed evaluate whether could enhance anti-TB drugs against

Language: Английский

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Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPK mt ) inhibition activity and molecular modelling studies

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 39(1)

Published: Sept. 11, 2024

New Biginelli adducts were rationalised,

Language: Английский

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1,3-Proton Transfer of Pyridoxal 5′-Phosphate Schiff Base in the Branched-Chain Aminotransferase: Concerted or Stepwise Mechanism?

The Journal of Physical Chemistry B, Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 22, 2023

The branched-chain aminotransferase from Mycobacterium tuberculosis (MtIlvE) is a pyridoxal 5′-phosphate (PLP) dependent enzyme, and it essential for the synthesis of amino acids. Ketimine an important intermediate in catalytic process. We have investigated mechanism ketimine formation energy landscape using multiple computational methods. It found that 1,3-proton transfer involved occurs through stepwise process rather than one-step Lys204 identified as key residue ligand binding base abstracts Cα proton PLP-Glu Schiff base, yielding carbanionic intermediate. first rate-limiting step with barrier 17.8 kcal mol–1. Our study disclosed detailed pathway external aldimine to ketimine, providing novel insights into other PLP-dependent enzymes.

Language: Английский

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Computational approaches: Atom-based 3D-QSAR, molecular docking, ADME-Tox, MD simulation and DFT to find novel multi-targeted Anti-tubercular agents

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: March 5, 2024

Abstract Tuberculosis (TB) has become the biggest threat towards human society due to rapid rise in resistance of causative bacteria Mycobacterium tuberculosis (MTB) against available anti-tubercular drugs. There is an urgent need design new multi-targeted agents overcome species MTB through computational tools. With this aim present work, a combination atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR), six-point pharmacophore (AHHRRR), and molecular docking analysis was performed on series fifty-eight agents. The generated QSAR model showed statistically significant correlation co-efficient R 2 , Q Pearson r-factor 0.9521, 0.8589, 0.8988 respectively indicating good predictive ability. Molecular study for data set compounds with two important target proteins, Enoyl acyl carrier protein reductase (InhA) (PDBID: 2NSD) Decaprenyl phosphoryl-β-D-Ribose 20-epimerase (DprE1) 4FDO). Using similarity search principle virtual screening 237 retrieved from Pubchem database identify potent multitargeted screened compound, MK3 highest score -9.2 − 8.3 Kj/mol both proteins InhA DprE1 were picked 100ns dynamic simulation using GROMACS. From generated, compound thermodynamic stability effective binding within active pocket without much deviation. result occupied orbital (HOMO) lowest unoccupied (LUMO) energy gap predicts reactivity identified molecule. Based above studies proposed can be successfully used development novel agent high affinity favourable ADME-T properties.

Language: Английский

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Research Progress on the Drug Resistance Mechanism of <i>Mycobacterium </i><i>tuberculosis</i>

Advances in Clinical Medicine, Journal Year: 2024, Volume and Issue: 14(07), P. 112 - 119

Published: Jan. 1, 2024

Language: Английский

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The Repurposing of FDA-Approved Drugs as FtsZ Inhibitors against Mycobacterium tuberculosis: An In Silico and In Vitro Study

Microorganisms, Journal Year: 2024, Volume and Issue: 12(8), P. 1505 - 1505

Published: July 23, 2024

Mycobacterium tuberculosis (Mtb), the causative pathogen of tuberculosis, remains one leading causes death from a single infectious agent. Furthermore, growing evolution to multi-drug-resistant (MDR) strains requires de novo identification drug targets for evaluating candidates or repurposing drugs. Hence, targeting FtsZ, an essential cell division protein, is promising target. Methods: Using in silico pharmacological repositioning strategy, four FDA-based drugs that bind catalytic site FtsZ were selected. The Alamar Blue colorimetric assay was used assess antimicrobial activity and effect on Mtb growth through curves. Bacterial load determined with vitro infection model using colony-forming units (CFU)/mL, cytotoxicity human monocyte-derived macrophages (MDMhs) assessed by flow cytometry. Results: Paroxetine nebivolol exhibited antimycobacterial against both reference TB MDR at concentration 25 µg/mL. paroxetine demonstrated significant reduction (p < 0.05) viable bacteria compared untreated group model. Conclusions: Collectively, our findings demonstrate use strategy help control infection.

Language: Английский

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Exploring the factors influencing the ketoenamine-enolimine tautomeric equilibrium of pyridoxal 5′-phosphate in branched-chain aminotransferases

Molecular Catalysis, Journal Year: 2024, Volume and Issue: 569, P. 114581 - 114581

Published: Oct. 7, 2024

Language: Английский

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Validation of DXS as an attractive drug target in mycobacteria

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

Abstract A rapid emergence in the incidences of Tuberculosis (TB) drug resistance undermines efforts to eradicate disease and strengthens calls for development new drugs with novel mechanisms action. In discovery, finding an attractive target is as important a good candidate. Hence more are made identify, validate prioritize targets TB discovery. Here, using CRISPRi technology, we showed that dxs1 transcriptional knockdown attenuated growth both Mycobacterium smegmatis tuberculosis cultures, effect was profound latter. Chemical supplementation medium 10 μM isoprenoid pyrophosphates, thiamine pyrophosphate failed rescue M. while partial observed addition menatetrenone, menaquinone derivative four isoprenyl groups. Similarly, culture could not be rescued by prenol isoprenol, which suggested lack salvage pathway mycobacteria. Importantly, context depleted mutants displayed four-fold sensitive towards mixture isoniazid, rifampicin ethambutol, suggesting inhibitors DXS enzyme or other MEP enzymes potentiate antimycobacterial first-line drugs. Additionally, depletion increased retardation mutant acidic pH under oxidative stress, conditions encountered activated macrophage compartments. Taken together, our results validated should prioritized developments on antitubercular agents.

Language: Английский

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Advancements and Challenges in Tuberculosis Drug Discovery: A Comprehensive Overview

Microbial Pathogenesis, Journal Year: 2024, Volume and Issue: 198, P. 107074 - 107074

Published: Nov. 7, 2024

Language: Английский

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