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Molecules (Basel, Switzerland) Aug 2023With the overuse and misuse of antimicrobial drugs, antibacterial resistance is becoming a critical global health problem. New antibacterial agents are effective...
With the overuse and misuse of antimicrobial drugs, antibacterial resistance is becoming a critical global health problem. New antibacterial agents are effective measures for overcoming the crisis of drug resistance. In this paper, a novel set of ciprofloxacin-indole/acetophenone hybrids was designed, synthesized, and structurally elucidated with the help of NMR and high-resolution mass spectrometry. The in vitro antibacterial activities of these hybrids against gram-positive and gram-negative pathogens, including four multidrug-resistant clinical isolates, were evaluated and compared with those of the parent drug ciprofloxacin (CIP). All the target compounds (MIC = 0.0625-32 μg/mL) exhibited excellent inhibitory activity against the strains tested. Among them, (MIC = 0.25-8 μg/mL) showed comparable or slightly less potent activity than CIP. The most active hybrid, (MIC = 0.0626-1 μg/mL), showed equal or higher activity than CIP. Moreover, compound showed superior bactericidal capability to CIP, with undetectably low resistance frequencies. Furthermore, molecular docking studies conducted showed that and CIP had a similar binding mode to DNA gyrase (). Thus, hybrids and could act as a platform for further investigations.
Topics: Ciprofloxacin; Molecular Docking Simulation; Anti-Bacterial Agents; DNA Gyrase; Indoles
PubMed: 37687154
DOI: 10.3390/molecules28176325 -
Nucleic Acids Research Oct 2023Gene context can have significant impact on gene expression but is currently not integrated in quantitative models of gene regulation despite known biophysical...
Gene context can have significant impact on gene expression but is currently not integrated in quantitative models of gene regulation despite known biophysical principles and quantitative in vitro measurements. Conceptually, the simplest gene context consists of a single gene framed by two topological barriers, known as the twin transcriptional-loop model, which illustrates the interplay between transcription and DNA supercoiling. In vivo, DNA supercoiling is additionally modulated by topoisomerases, whose modus operandi remains to be quantified. Here, we bridge the gap between theory and in vivo properties by realizing in Escherichia coli the twin transcriptional-loop model and by measuring how gene expression varies with promoters and distances to the topological barriers. We find that gene expression depends on the distance to the upstream barrier but not to the downstream barrier, with a promoter-dependent intensity. We rationalize these findings with a first-principle biophysical model of DNA transcription. Our results are explained if TopoI and gyrase both act specifically, respectively upstream and downstream of the gene, with antagonistic effects of TopoI, which can repress initiation while facilitating elongation. Altogether, our work sets the foundations for a systematic and quantitative description of the impact of gene context on gene regulation.
PubMed: 37667073
DOI: 10.1093/nar/gkad688 -
Heliyon Aug 2023The primary objective of this research work was to study the antibacterial effects of essential oil (EO) against various drug resistant bacterial pathogens along with...
The primary objective of this research work was to study the antibacterial effects of essential oil (EO) against various drug resistant bacterial pathogens along with studying the molecular docking interactions of the major components of the EO with the key bacterial proteins/enzymes. Gas chromatography-mass spectrometry was used to analyse the chemical composition of the EO. The initial antibacterial screening was performed by using disc diffusion and microdilution methods. Scanning electron microscopy was also performed in order to study effects of the EO on bacterial cell morphology. Further, molecular docking studies were performed using Autodock Vina and results were visualised by BIOVIA Discovery Studio. The chemical composition of the EO showed the presence of 15 components with citronellal, terpinene-4-ol, α-phellandrene and 1,8-cineole as the major components of the EO. Results indicated that the EO of exhibited dose-dependent as well as time dependent antibacterial effects. The scanning electron microscopy indicated that the EO led to membrane rupture and permeabilization of the bacterial cells. Molecular docking studies indicated that the major compounds of the EO (citronellal and terpinene-4ol) showed strong interactions with the active site of the bacterial DNA gyrase enzyme explaining the antibacterial mode of action of the EO. Ciprofloxacin was also used for docking which showed stronger interactions with the target protein than citronellal or terpinene-4-ol. In conclusion, the major findings of the current study were that the EO of causes bacterial membrane rupture and permeabilization, shows time-dependent and dose-dependent antibacterial action, along with interacting with crucial bacterial enzyme viz., DNA gyrase as indicated by molecular docking studies.
PubMed: 37636470
DOI: 10.1016/j.heliyon.2023.e18742 -
Molecules (Basel, Switzerland) Aug 2023We report herein the synthesis, docking studies and biological evaluation of a series of new 4-chloro-2-((5-aryl-1,3,4-oxadiazol-2-yl)amino)phenol analogues (). The new...
We report herein the synthesis, docking studies and biological evaluation of a series of new 4-chloro-2-((5-aryl-1,3,4-oxadiazol-2-yl)amino)phenol analogues (). The new compounds were designed based on the oxadiazole-linked aryl core of tubulin inhibitors of IMC-038525 and IMC-094332, prepared in five steps and further characterized via spectral analyses. The anticancer activity of the compounds was assessed against several cancer cell lines belonging to nine different panels as per National Cancer Institute (NCI US) protocol. 4-Chloro-2-((5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)phenol () demonstrated significant anticancer activity against SNB-19 (PGI = 65.12), NCI-H460 (PGI = 55.61), and SNB-75 (PGI = 54.68) at 10 µM. The compounds were subjected to molecular docking studies against the active site of the tubulin-combretastatin A4 complex (PDB ID: 5LYJ); they displayed efficient binding and ligand (with docking score = -8.030 kcal/mol) lay within the hydrophobic cavity surrounded by important residues Leu252, Ala250, Leu248, Leu242, Cys241, Val238, Ile318, Ala317, and Ala316. Furthermore, the antibacterial activity of some of the compounds was found to be promising. 4-Chloro-2-((5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)amino)phenol () displayed the most promising antibacterial activity against both Gram-negative as well as Gram-positive bacteria with MICs of 8 µg/mL and a zone of inhibition ranging from 17.0 ± 0.40 to 17.0 ± 0.15 mm at 200 µg/mL; however, the standard drug ciprofloxacin exhibited antibacterial activity with MIC values of 4 µg/mL.
Topics: Phenol; Molecular Docking Simulation; Phenols; Anti-Bacterial Agents
PubMed: 37630338
DOI: 10.3390/molecules28166086 -
Antibiotics (Basel, Switzerland) Jul 2023The extensive use of fluoroquinolones has been consequently accompanied by the emergence of bacterial resistance, which triggers the necessity to discover new compounds.... (Review)
Review
The extensive use of fluoroquinolones has been consequently accompanied by the emergence of bacterial resistance, which triggers the necessity to discover new compounds. Delafloxacin is a brand-new anionic non-zwitterionic fluoroquinolone with some structural particularities that give it attractive proprieties: high activity under acidic conditions, greater in vitro activity against Gram-positive bacteria-even those showing resistance to currently-used fluoroquinolones-and nearly equivalent affinity for both type-II topoisomerases (i.e., DNA gyrase and topoisomerase IV). During phases II and III clinical trials, delafloxacin showed non-inferiority compared to standard-of-care therapy in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, which resulted in its approval in 2017 by the Food and Drug Administration for indications. Thanks to its overall good tolerance, its broad-spectrum in vitro activity, and its ease of use, it could represent a promising molecule for the treatment of bacterial infections.
PubMed: 37627661
DOI: 10.3390/antibiotics12081241 -
RSC Advances Aug 2023Herein, BiO quantum dots (QDs) have been synthesized and doped with various concentrations of graphitic carbon nitride (g-CN) and a fixed amount of carbon spheres (CS)...
Herein, BiO quantum dots (QDs) have been synthesized and doped with various concentrations of graphitic carbon nitride (g-CN) and a fixed amount of carbon spheres (CS) using a co-precipitation technique. XRD analysis confirmed the presence of monoclinic structure along the space group 2/ and 2/. Various functional groups and characteristic peaks of (Bi-O) were identified using FTIR spectra. QDs morphology of BiO showed agglomeration with higher amounts of g-CN by TEM analysis. HR-TEM determined the variation in the -spacing which increased with increasing dopants. These doping agents were employed to reduce the exciting recombination rate of BiO QDs by providing more active sites which enhance antibacterial activity. Notably, (6 wt%) g-CN/CS-doped BiO exhibited considerable antimicrobial potential in opposition to at higher values of concentrations relative to ciprofloxacin. The (3 wt%) g-CN/CS-doped BiO exhibits the highest catalytic potential (97.67%) against RhB in a neutral medium. The compound g-CN/CS-BiO has been suggested as a potential inhibitor of β-lactamase and DNA gyrase based on the findings of a molecular docking study that was in better agreement with bactericidal activity.
PubMed: 37622014
DOI: 10.1039/d3ra04664h -
Research in Pharmaceutical Sciences 2023The incidence of antibiotic resistance rapidly emerges over the globe. In the present study, the synthesis of thiourea derivatives as antibacterial agents and their...
BACKGROUND AND PURPOSE
The incidence of antibiotic resistance rapidly emerges over the globe. In the present study, the synthesis of thiourea derivatives as antibacterial agents and their biological evaluation are reported.
EXPERIMENTAL APPROACH
Preliminary studies were done by molecular docking of four analogs of 1-allyl-3-benzoylthiourea, clorobiocin, and ciprofloxacin on the DNA gyrase subunit B receptor (PDB: 1KZN). The nucleophilic substitution reaction of benzoyl chloride analogs to the allylthiourea yielded four 1-allyl-3-benzoylthiourea analogs (Cpd 1-4). The reactions were done by a modified Schotten Baumann method. The antimicrobial activities were determined using the agar dilution method against methicillin-resistant (MRSA), typhi, , and .
FINDINGS/RESULTS
The study showed that Cpd 1-4 possesses a good interaction on the DNA gyrase subunit B receptor compared to the ciprofloxacin. Cpd 3 had the best binding affinity with a rerank score of - 91.2304. Although the candidate compounds showed unsatisfactory antibacterial activity, they indicated an increasing trend of growth inhibition along with the increment of concentration. Cpd 1 and 4 exhibited antibacterial activities against MRSA with a minimum inhibitory concentration value of 1000 µg/mL, better compared to the other compounds.
CONCLUSION AND IMPLICATION
Despite lacking antibacterial activity, all the synthesized compounds showed an increased trend of growth inhibition along with the increment of concentration. Therefore, additional development should be implemented to the compounds of interest in which optimization of lipophilicity and steric properties are suggested.
PubMed: 37614619
DOI: 10.4103/1735-5362.378084 -
RSC Advances Aug 2023The extracellular matrix (ECM) undergoes constant physiochemical change. User-programmable biomaterials afford exciting opportunities to study such dynamic processes ....
The extracellular matrix (ECM) undergoes constant physiochemical change. User-programmable biomaterials afford exciting opportunities to study such dynamic processes . Herein, we introduce a protein-polymer hydrogel whose stiffness can be pharmacologically and reversibly regulated with conventional antibiotics. Specifically, a coumermycin-mediated homodimerization of gel-tethered DNA gyrase subunit B (GyrB) creates physical crosslinking and a rheological increase in hydrogel mechanics, while competitive displacement of coumermycin with novobiocin returns the material to its softened state. These unique platforms could potentially be modulated and are expected to prove useful in elucidating the effects of ECM-presented mechanical signals on cell function.
PubMed: 37588975
DOI: 10.1039/d3ra04046a -
RSC Advances Aug 2023Compounds bearing thiazole and chalcone groups have been reported to be excellent leads for antibacterial, antitubercular and anticancer activities. In view of this, we...
Compounds bearing thiazole and chalcone groups have been reported to be excellent leads for antibacterial, antitubercular and anticancer activities. In view of this, we performed quantitative structure-activity relationship studies using QSARINS for dataset preparation and for developing validated QSAR models that can predict novel series of thiazole-chalcone hybrids and further evaluate them for bioactivities. The molecular descriptors AATS8i, AVP-1, MoRSEE17 and GATSe7 were found to be active in predicting the structure-activity relationship. Molecular docking and dynamics simulation studies of the developed leads have shown insights into structural analysis. Furthermore, computational studies using AutoDock and Desmond predicted the key binding interactions responsible for the activity and the SwissADME tool computed the drug likeliness properties. The lead compound 178 generated through this study creates a route for the optimization and development of novel drugs against tuberculosis infections. RMSD, RMSF, RoG, H-bond and SASA analysis confirmed the stable binding of compound 178 with the 6J90 structure. In addition, MM-PBSA and MM-GBSA also confirm the docking results. We propose the designed compound 178 as the best theoretical lead, which may further be experimentally studied for selective inhibition.
PubMed: 37583661
DOI: 10.1039/d3ra00732d -
RSC Advances Aug 2023A new library of peptide-heterocycle hybrids consisting of an indole-3-carboxylic acid constituent conjugated with short dipeptide motifs was designed and synthesized by...
A novel series of dipeptide derivatives containing indole-3-carboxylic acid conjugates as potential antimicrobial agents: the design, solid phase peptide synthesis, biological evaluation, and molecular docking study.
A new library of peptide-heterocycle hybrids consisting of an indole-3-carboxylic acid constituent conjugated with short dipeptide motifs was designed and synthesized by using the solid phase peptide synthesis methodology. All the synthesized compounds were characterized by spectroscopic techniques. Additionally, the synthesized compounds were subjected to antimicrobial activities. Two Gram-negative bacteria ( and ) and two Gram-positive ( and ) were used for the evaluation of the antibacterial activity of the targeted dipeptide derivatives. Good antibacterial activity was observed for the screened analogues by comparing their activities with that of ciprofloxacin, the standard drug. Also, two fungi ( and ) were employed for the evaluation of the antifungal activity of the synthesized compounds. When compared to the standard drug Fluconazole, it was observed that the screened analogues exhibited good antifungal activity. In continuation, all the synthesized derivatives were subjected to integrated molecular docking studies and molecular dynamics simulations to investigate binding affinities, intermolecular interaction networks, and conformational flexibilities with deoxyribonucleic acid (DNA) gyrase and lanosterol-14-alpha demethylase. The molecular docking studies revealed that indole-3-carboxylic acid conjugates exhibited encouraging binding interaction networks and binding affinity with DNA gyrase and lanosterol-14 alpha demethylase to show antibacterial and antifungal activity, respectively. Such synthesis, biological activity, molecular dynamics simulations, and molecular docking studies of short peptides with an indole conjugate unlock the door for the near future advancement of novel medicines containing peptide-heterocycle hybrids with the ability to be effective as antimicrobial agents.
PubMed: 37583660
DOI: 10.1039/d3ra04100j