scholarly journals Synthesis, In Silico and In Vitro Antimicrobial Evaluation of Cyanoketene S,N-Acetals and Their Pyrazoles Against Staphylococcus Aureus DNA Gyrase Enzyme

2021 ◽  
Vol 0 (0) ◽  
pp. 0-0
Author(s):  
Shimaa Ali ◽  
Ahmed H.I. Faraag ◽  
Hossam Elgiushy ◽  
Taghred Said ◽  
ahmed askar ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
In Silico ◽  
Dna Gyrase ◽  
Antimicrobial Evaluation

scholarly journals Design of a novel DNA Gyrase B inhibitor with a rhodanine scaffold: in silico and in vitro approaches

2021 ◽  
Author(s):  
Akhila Pudipeddi ◽  
Sahana Vasudevan ◽  
Karthi Shanmugam ◽  
Alex Stanley ◽  
Vairaprakash Pothiappan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
In Silico ◽  
De Novo ◽  
Ligand Design ◽  
Dna Gyrase ◽  
Cross Resistance ◽  
Screening Process ◽  
Bacterial Enzyme ◽  
Time Kill

AbstractMethicillin-resistant Staphylococcus aureus (MRSA) and vancomycin intermediate-resistant Staphylococcus aureus (VRSA) is one among the WHO high priority pathogens. Among these two, MRSA is the most globally documented pathogen that necessitates the pressing demand for new classes of anti-MRSA drugs. Bacterial gyrase targeted therapeutics are unique strategies to overcome cross-resistance as they are present only in bacteria and absent in higher eukaryotes. The GyrB subunit is essential for the catalytic functions of the bacterial enzyme DNA Gyrase, thereby constituting a promising druggable target. The current study performed a structure-based virtual screening to designing GyrB target-specific candidate molecules. The de novo ligand design of novel hit molecules was performed using a rhodanine scaffold. Through a systematic in silico screening process, the hit molecules were screened for their synthetic accessibility, drug likeliness and pharmacokinetics properties in addition to its target specific interactions. Of the total 374 hit molecules obtained through de novo ligand design, qsl-304 emerged as the most promising ligand. qsl-304 was synthesized through a one-step chemical synthesis procedure, and the in vitro activity was proven, with an IC50 of 31.23 μg/mL against the novobiocin resistant clinical isolate of Staphylococcus aureus sa-P2003. Further studies on time-kill kinetics showed the bacteriostatic nature with the diminished recurrence of resistance.

scholarly journals Differential behaviors of Staphylococcus aureus and Escherichia coli type II DNA topoisomerases.

1996 ◽  
Vol 40 (12) ◽  
pp. 2714-2720 ◽  
Author(s):  
F Blanche ◽  
B Cameron ◽  
F X Bernard ◽  
L Maton ◽  
B Manse ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Strong Support ◽  
Dna Gyrase ◽  
Dna Supercoiling ◽  
Type Ii ◽  
Topoisomerase Iv ◽  
E Coli ◽  
Dna Relaxation

Staphylococcus aureus gyrA and gyrB genes encoding DNA gyrase subunits were cloned and coexpressed in Escherichia coli under the control of the T7 promoter-T7 RNA polymerase system, leading to soluble gyrase which was purified to homogeneity. Purified gyrase was catalytically indistinguishable from the gyrase purified from S. aureus and did not contain detectable amounts of topoisomerases from the E. coli host. Topoisomerase IV subunits GrlA and GrlB from S. aureus were also expressed in E. coli and were separately purified to apparent homogeneity. Topoisomerase IV, which was reconstituted by mixing equimolar amounts of GrlA and GrlB, had both ATP-dependent decatenation and DNA relaxation activities in vitro. This enzyme was more sensitive than gyrase to inhibition by typical fluoroquinolone antimicrobial agents such as ciprofloxacin or sparfloxacin, adding strong support to genetic studies which indicate that topoisomerase IV is the primary target of fluoroquinolones in S. aureus. The results obtained with ofloxacin suggest that this fluoroquinolone could also primarily target gyrase. No cleavable complex could be detected with S. aureus gyrase upon incubation with ciprofloxacin or sparfloxacin at concentrations which fully inhibit DNA supercoiling. This suggests that these drugs do not stabilize the open DNA-gyrase complex, at least under standard in vitro incubation conditions, but are more likely to interfere primarily with the DNA breakage step, contrary to what has been reported with E. coli gyrase. Both S. aureus gyrase-catalyzed DNA supercoiling and S. aureus topoisomerase IV-catalyzed decatenation were dramatically stimulated by potassium glutamate or aspartate (500- and 50-fold by 700 and 350 mM glutamate, respectively), whereas topoisomerase IV-dependent DNA relaxation was inhibited 3-fold by 350 mM glutamate. The relevance of the effect of dicarboxylic amino acids on the activities of type II topoisomerases is discussed with regard to the intracellular osmolite composition of S. aureus.

scholarly journals Synthesis, Characterization and in vitro Antimicrobial Evaluation of Chalconeimine Derivatives as Potential Inhibitors against Enzymes Produced from S. aureus: A Computational Approach

2019 ◽  
Vol 31 (10) ◽  
pp. 2157-2164
Author(s):  
B. Prithivirajan ◽  
M. Jebastin Sonia Jas ◽  
G. Marimuthu
Keyword(s):  
Antibacterial Agents ◽  
Dna Gyrase ◽  
Bacterial Strains ◽  
Bacterial Proteins ◽  
Antibiotic Drug ◽  
In Vitro Antibacterial Activity ◽  
Antimicrobial Evaluation ◽  
Potential Inhibitors ◽  
Gyrase Inhibitors

(Z)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-(difluoromethoxy)-3-hydroxyphenyl)prop-2-en-1-one hydrazone derivatives pronounced in this manuscript represents a new collection of antibacterial agents in addition to the DNA gyrase inhibitors. Efforts had been made to synthesize those chalcone-hydrazone derivatives (4a-e) in good yields. The literature survey confirms that nano-ZnO as heterogeneous catalyst has obtained big interest because of its ecofriendly nature and has been explored as a effective catalyst for several organic ameliorations. Subsequently, induced by way of these observations and in continuation to our interest in organic synthesis with using nanocatalyst. in vitro Antibacterial activity has been evaluated towards Gram-positive and Gram-negative bacterial strains for all compounds. So one can discover the affinity to bacterial proteins docking have a look at have been carried out for 5 synthesized derivatives, antibiotic drug and co-crystallized ligands with special mechanism of action DNA gyrase B and methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) the usage of AutoDock 4.

Prediction Mechanism of Nevadensin as Antibacterial Agent against S. sanguinis: In vitro and In silico Studies

2021 ◽  
Vol 24 ◽  
Author(s):  
Aldina Amalia Nur Shadrina ◽  
Yetty Herdiyati ◽  
Ika Wiani ◽  
Mieke Hemiawati Satari ◽  
Dikdik Kurnia
Keyword(s):  
Antibacterial Activity ◽  
Molecular Docking ◽  
Dental Caries ◽  
Binding Affinity ◽  
In Silico ◽  
Antibacterial Agent ◽  
In Silico Analysis ◽  
Dna Gyrase ◽  
Silico Analysis

Background: Streptococcus sanguinis can contribute to tooth demineralization, which can lead to dental caries. Antibiotics used indefinitely to treat dental caries can lead to bacterial resistance. Discovering new antibacterial agents from natural products like Ocimum basilicum will help combat antibiotic resistance. In silico analysis (molecular docking) can help determine the lead compound by studying the molecular interaction between the drug and the target receptor (MurA enzyme and DNA gyrase). It is a potential candidate for antibacterial drug development. Objective: The research objective is to isolate the secondary metabolite of O. basilicum extract that has activity against S. sanguinis through in vitro and in silico analysis. Methods: n-Hexane extract of O. basilicum was purified by combining column chromatography with bioactivity-guided. The in vitro antibacterial activity against S. sanguinis was determined using the disc diffusion and microdilution method, while molecular docking simulation of nevadensin (1) with MurA enzyme and DNA gyrase was performed used PyRx 0.8 program. Results: Nevadensin from O. basilicum was successfully isolated and characterized by spectroscopic methods. This compound showed antibacterial activity against S. sanguinis with MIC and MBC values of 3750 and 15000 μg/mL, respectively. In silico analysis showed that the binding affinity to MurA was -8.5 Kcal/mol, and the binding affinity to DNA gyrase was -6.7 Kcal/mol. The binding of nevadensin-MurA is greater than fosfomycin-MurA. Otherwise, Nevadensin-DNA gyrase has a weaker binding affinity than fluoroquinolone-DNA gyrase and chlorhexidine-DNA gyrase. Conclusion: Nevadensin showed potential as a new natural antibacterial agent by inhibiting the MurA enzyme rather than DNA gyrase.

scholarly journals Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Letícia Tiburcio Ferreira ◽  
Juliana Rodrigues ◽  
Gustavo Capatti Cassiano ◽  
Tatyana Almeida Tavella ◽  
Kaira Cristina Peralis Tomaz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
In Silico ◽  
Antimalarial Activity ◽  
Drug Repositioning ◽  
Dna Gyrase ◽  
Plasmodium Yoelii ◽  
Computer Assisted ◽  
Content Type

ABSTRACT Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

scholarly journals Design, Synthesis, and Antimicrobial Evaluation of New Annelated Pyrimido[2,1-c][1,2,4]triazolo[3,4-f][1,2,4]triazines

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1339 ◽  
Author(s):  
Islam H. El Azab ◽  
Nadia A.A. Elkanzi
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Positive Control ◽  
Design Synthesis ◽  
Aspergillus Brasiliensis ◽  
In Vitro Investigation ◽  
Bacillus Subtilis Atcc ◽  
Antimicrobial Evaluation

A series of 34 new pyrimido[2,1-c][1,2,4]triazine-3,4-diones were synthesized and fully characterized using IR, NMR, MS, and microanalytical analysis. In vitro investigation of 12 compounds of this series revealed promising antimicrobial activity of the conjugates 15a and 15f–j that were tagged with electron-withdrawing groups, with sensitivities ranging from 77% to as high as 100% of the positive control. The investigation of antimicrobial activity included Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6535, Pseudomonas aeruginosa ATCC 27853, and Escherichia coli ATCC 8739 (EC), and fungal strains Candida albicans ATCC 10231 and Aspergillus brasiliensis ATCC 16404.

scholarly journals In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Studies of the Mode of Action in Staphylococcus aureus

2008 ◽  
Vol 52 (7) ◽  
pp. 2313-2323 ◽  
Author(s):  
Gregory T. Robertson ◽  
Eric J. Bonventre ◽  
Timothy B. Doyle ◽  
Qun Du ◽  
Leonard Duncan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Rna Polymerase ◽  
Mode Of Action ◽  
Bacterial Infections ◽  
Dna Gyrase ◽  
Topoisomerase Iv ◽  
Dna Topoisomerase ◽  
Resistant Variant ◽  
Proven Efficacy

ABSTRACT Rifamycins have proven efficacy in the treatment of persistent bacterial infections. However, the frequency with which bacteria develop resistance to rifamycin agents restricts their clinical use to antibiotic combination regimens. In a program directed toward the synthesis of rifamycins with a lower propensity to elicit resistance development, a series of compounds were prepared that covalently combine rifamycin and quinolone pharmacophores to form stable hybrid antibacterial agents. We describe mode-of-action studies with Staphylococcus aureus of CBR-2092, a novel hybrid that combines the rifamycin SV and 4H-4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibited rifampin-like potency as an inhibitor of RNA polymerase, was an equipotent (balanced) inhibitor of DNA gyrase and DNA topoisomerase IV, and retained activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirmed that CBR-2092 has rifampin-like effects on RNA synthesis in rifampin-susceptible strains and quinolone-like effects on DNA synthesis in rifampin-resistant strains. Studies of mutant strains that exhibited reduced susceptibility to CBR-2092 further substantiated RNA polymerase as the primary cellular target of CBR-2092, with DNA gyrase and DNA topoisomerase IV being secondary and tertiary targets, respectively, in strains exhibiting preexisting rifampin resistance. In contrast to quinolone comparator agents, no strains with altered susceptibility to CBR-2092 were found to exhibit changes consistent with altered efflux properties. The combined data indicate that CBR-2092 may have potential utility in monotherapy for the treatment of persistent S. aureus infections.

scholarly journals Synthesis, in vitro Antimicrobial Evaluation, Molecular Docking Studies and ADME Prediction of Furan-2-yl-Morpholinophenylpyrimidine Derivatives

2021 ◽  
Vol 33 (5) ◽  
pp. 1090-1098
Author(s):  
M.R. Ezhilarasi ◽  
A.B. Senthieel Khumar ◽  
P. Elavarasan
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Docking Studies ◽  
In Silico Docking ◽  
E Coli ◽  
Biological Studies ◽  
Antimicrobial Evaluation ◽  
Microbial Strains ◽  
In Silico Molecular Docking

A new series of novel 4-(furan-2-yl)-6-(4-morpholinophenyl)pyrimidine-amines (4a-c) were synthesized and characterized by elemental analysis and spectral analysis like IR, 1D 1H & 13C NMR. The synthesized compounds 4a-c were evaluated for their biological studies. The zone of inhibitions were examined for synthesized compounds 4a-c besides the identical set of microbial strains, especially that compound 4a against S. aureus, S. pyogenes, E. coli, compound 4b against P. aeruginosa has excellent antibacterial activity. Compound 4c shows good inhibition against C. albicans. Also in silico molecular docking and ADME predictions were carried for all the compounds. The docking studies were examined by two different proteins like 1UAG protein and 1OQA protein. in silico docking provides of the compounds have good docking score compared with the standard. In the ADME predictions all the compounds were met criteria. The synthesized compounds all of them obeyed the drug-likeness properties.

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