Bioisosteric modification of Linezolid identified the potential <i>M. tuberculosis</i> protein synthesis inhibitors to overcome the myelosuppression and serotonergic toxicity associated with Linezolid in the treatment of the multi-drug resistance tuberculosis (MDR-TB)

Linezolid is the first and only oxazolidinone antibacterial drug was approved in the last 35 years. It exhibits bacteriostatic efficacy against M. tuberculosis and is a crucial constituent of the BPaL regimen (Bedaquiline, Pretomanid, and Linezolid), which was authorized by the FDA in 2019 for the treatment of XDR-TB or MDR-TB. Despite its unique mechanism of action, Linezolid carries a considerable risk of toxicity, including myelosuppression and serotonin syndrome (SS), which is caused by inhibition of mitochondrial protein synthesis (MPS) and monoamine oxidase (MAO), respectively. Based on the structure toxicity relationship (STR) of Linezolid, in this work, we used a bioisosteric replacement approach to optimize the structure of Linezolid at the C-ring and/or C-5 position for myelosuppression and serotogenic toxicity. Extensive hierarchical multistep docking, drug likeness prediction, molecular binding interactions analyses, and toxicity assessment identified three promising compounds (3071, 7549 and 9660) as less toxic potential modulators of Mtb EthR protein. Compounds 3071, 7549 and 9660 were having the significant docking score of −12.696 Kcal/mol, −12.681 Kcal/mol and −15.293 Kcal/mol towards the Mtb EthR protein with less MAO-A and B affinity [compound 3071: MAO A (-4.799 Kcal/mol) and MAO B (-6.552 Kcal/mol); compound 7549: MAO A (> −2.00 Kcal/mol) and MAO B (> −2.00 Kcal/mol) and compound 9660: MAO A (> −5.678 Kcal/mol) and MAO B (> −6.537Kcal/mol) and none of them shown the Leukopenia as a side effect due to the Myelosuppression. The MD simulation results and binding free energy estimations correspond well with docking analyses, indicating that the proposed compounds bind and inhibit the EthR protein more effectively than Linezolid. The quantum mechanical and electrical characteristics were evaluated using density functional theory (DFT), which also demonstrated that the proposed compounds are more reactive than Linezolid. Communicated by Ramaswamy H. Sarma</p

Computational modelling of potential Zn-sensitive non-β-lactam inhibitors of imipenemase-1 (IMP-1)

Antibiotic resistance (AR) remains one of the leading global health challenges, mostly implicated in disease-related deaths. The Enterobacteriaceae-producing metallo-β-lactamases (MBLs) are critically involved in AR pathogenesis through Zn-dependent catalytic destruction of β-lactam antibiotics, yet with limited successful clinical inhibitors. The efficacy of relevant broad-spectrum β-lactams including imipenem and meropenem are seriously challenged by their susceptibility to the Zn-dependent carbapenemase hydrolysis, as such, searching for alternatives remains imperative. In this study, computational molecular modelling and virtual screening methods were extensively applied to identify new putative Zn-sensitive broad-spectrum inhibitors of MBLs, specifically imipenemase-1 (IMP-1) from the IBScreen database. Three ligands, STOCK3S-30154, STOCK3S-30418 and STOCK3S-30514 selectively displayed stronger binding interactions with the enzymes compared to reference inhibitors, imipenem and meropenem. For instance, the ligands showed molecular docking scores of −9.450, −8.005 and −10.159 kcal/mol, and MM-GBSA values of −40.404, −31.902 and −33.680 kcal/mol respectively against the IMP-1. Whereas, imipenem and meropenem showed docking scores of −9.038 and −10.875 kcal/mol, and MM-GBSA of −31.184 and −32.330 kcal/mol respectively against the enzyme. The ligands demonstrated good thermodynamic stability and compactness in complexes with IMP-1 throughout the 100 ns molecular dynamics (MD) trajectories. Interestingly, their binding affinities and stabilities were significantly affected in contacts with the remodelled Zn-deficient IMP-1, indicating sensitivity to the carbapenemase active Zn site, however, with non-β-lactam scaffolds, tenable to resist catalytic hydrolysis. They displayed ideal drug-like ADMET properties, thus, representing putative Zn-sensitive non-β-lactam inhibitors of IMP-1 amenable for further experimental studies. Communicated by Ramaswamy H. Sarma</p

Data_Sheet_1_Unveiling chlorpyrifos mineralizing and tomato plant-growth activities of Enterobacter sp. strain HSTU-ASh6 using biochemical tests, field experiments, genomics, and in silico analyses.docx

The chlorpyrifos-mineralizing rice root endophyte Enterobacter sp. HSTU-ASh6 strain was identified, which enormously enhanced the growth of tomato plant under epiphytic conditions. The strain solubilizes phosphate and grew in nitrogen-free Jensen’s medium. It secreted indole acetic acid (IAA; 4.8 mg/mL) and ACC deaminase (0.0076 μg/mL/h) and hydrolyzed chlorpyrifos phosphodiester bonds into 3,5,6-trichloro-2-pyridinol and diethyl methyl-monophosphate, which was confirmed by Gas Chromatography – Tandem Mass Spectrometry (GC–MS/MS) analysis. In vitro and in silico (ANI, DDH, housekeeping genes and whole genome phylogenetic tree, and genome comparison) analyses confirmed that the strain belonged to a new species of Enterobacter. The annotated genome of strain HSTU-ASh6 revealed a sets of nitrogen-fixing, siderophore, acdS, and IAA producing, stress tolerance, phosphate metabolizing, and pesticide-degrading genes. The 3D structure of 28 potential model proteins that can degrade pesticides was validated, and virtual screening using 105 different pesticides revealed that the proteins exhibit strong catalytic interaction with organophosphorus pesticides. Selected docked complexes such as α/β hydrolase–crotoxyphos, carboxylesterase–coumaphos, α/β hydrolase–cypermethrin, α/β hydrolase–diazinon, and amidohydrolase–chlorpyrifos meet their catalytic triads in visualization, which showed stability in molecular dynamics simulation up to 100 ns. The foliar application of Enterobacter sp. strain HSTU-ASh6 on tomato plants significantly improved their growth and development at vegetative and reproductive stages in fields, resulting in fresh weight and dry weight was 1.8–2.0-fold and 1.3–1.6-fold higher in where urea application was cut by 70%, respectively. Therefore, the newly discovered chlorpyrifos-degrading species Enterobacter sp. HSTU-ASh6 could be used as a smart biofertilizer component for sustainable tomato cultivation.</p

Anti-inflammatory biomolecular activity of chlorinated-phenyldiazenyl-naphthalene-2-sulfonic acid derivatives: perception from DFT, molecular docking, and molecular dynamic simulation

In this study, two novel derivatives of naphthalene-2-sulfonic acid: 6-(((1S,5R)-3,5-dichloro-2,4,6-triazabicyclo [z3.1.0]hex-3-en-1-yl)amino)-5-((E)-phenyldiazenyl)naphthalene-2-sulfonic acid (DTPS1) and (E)-6-((4,6-dichloro-1,3,5-triazine2-yl)amino)-4-hydroxy-3-(phenyldiazenyl)naphthalene-2-sulfonic acid (DTPS2) have been synthesized and characterized using FT-IR, UV-vis, and NMR spectroscopic techniques. Applying density functional theory (DFT) at the B3LYP, APFD, PBEPBE, HCTH, TPSSTPSS, and ωB97XD/aug-cc-pVDZ level of theories for the electronic structural properties. In-vitro analysis, molecular docking, molecular dynamic (MD) simulation of the compounds was conducted to investigate the anti-inflammatory potential using COXs enzymes. Docking indicates binding affinity of −9.57, −9.60, −6.77 and −7.37 kcal/mol for DTPS1, DTPS2, Ibuprofen and Diclofenac which agrees with in-vitro assay. Results of MD simulation, indicates sulphonic group in DTPS1 has > 30% interaction with the hydroxyl and oxygen atoms in amino acid residues, but > 35% interaction with the DTPS2. It can be said that the DTPS1 and DTPS2 can induce inhibitory effect on COXs to halt biosynthesis of prostaglandins (PGs), a chief mediator of inflammation and pain in mammals. Communicated by Ramaswamy H. Sarma</p

Synthesis and Evaluation of Biological Activities for a Novel 1,2,3,4-Tetrahydroisoquinoline Conjugate with Dipeptide Derivatives: Insights from Molecular Docking and Molecular Dynamics Simulations

Peptide synthesis has opened new frontiers in the quest for bioactive molecules with limitless biological applications. This study presents the synthesis of a series of novel isoquinoline dipeptides using advanced spectroscopic techniques for characterization. These compounds were designed with the goal of discovering unexplored biological activities that could contribute to the development of novel pharmaceuticals. We evaluated the biological activities of novel compounds including their antimicrobial, antibacterial, and antifungal properties. The results show promising activity against Escherichia coli and potent antibacterial activity against MTCC 443 and MTCC 1688. Furthermore, these compounds demonstrate strong antifungal activity, outperforming existing standard drugs. Computational binding affinity studies of tetrahydroisoquinoline-conjugated dipeptides against E. coli DNA gyrase displayed significant binding interactions and binding affinity, which are reflected in antimicrobial activities of compounds. Our integrative significant molecular findings from both wet and dry laboratories would help pave a path for the development of antimicrobial therapeutics. The findings suggest that these isoquinoline-conjugated dipeptides could be excellent candidates for drug development, with potential applications in the fight against bacterial and fungal infections. This research represents an exciting step forward in the field of peptide synthesis and its potential to discover novel bioactive molecules with significant implications for human health