Target DNA Gyrase Research Articles

New N-amino-5-cyano-6-pyridones as antimicrobial small molecules endowed with DNA gyrase a inhibitory activity: design, one-pot synthesis, biological assessment and in silico insights.

A set of innovative N-amino-5-cyano-6-pyridones derivatives was developed and produced using one-pot three-component procedures. The evaluated molecules were examined for their antimicrobial efficacy. Based on the acquired findings, most of the investigated compounds had promising antimicrobial properties. Out of these derivatives of 3-cyanopyridine, compounds 3d and 3e exhibited minimum inhibitory concentrations (MIC) of 3.91µg/mL against E.coli. In vitro evaluation of DNA gyrase A displayed that molecule 3d exhibited promising potency as an inhibitor, with an IC50 value of 1.68µg/mL compared to ciprofloxacin (IC50 = 0.45µg/mL). Furthermore, it was observed that molecule 3e exhibited a moderate inhibitory effect, as indicated by its IC50 value of 3.77µg/mL. A kinetics study conducted to assess the time required to kill E. coli bacteria demonstrated that gentamycin and compounds 3d and 3e exhibited bactericidal effects within a time frame of 90-120min. Based on the ADME predictions, compounds 3d and 3e are expected to have favorable oral bioavailability and are unlikely to penetrate the blood-brain barrier. Computational mutagenicity and tumorigenicity studies were conducted on compounds 3d and 3e. The molecular docking investigation has conclusively demonstrated the binding of compounds 3d and 3e to the target DNA gyrase A enzyme, further reinforcing the existing data.

Synthesis, enzyme inhibition, and docking studies of new schiff bases of disalicylic acid methylene-based derivatives as dual-target antibacterial agents

IntroductionBacteria have acquired resistance to almost all antibiotics currently in use due to their extensive, broad, and improper utilization over a prolonged period. DNA gyrase and DHFR exhibit significant promise as targets for antibacterial therapeutics.MethodsWe have developed a series of disalicylic acid methylene/Schiff bases hybrids (6a-l) that function as antibacterial agents by targeting DNA gyrase and DHFR.Results and discussionThe findings showed that 6a-l have significant antibacterial activity against both Gram-positive and Gram-negative bacteria, with inhibition zones (IZ) comparable to or even higher than the reference Ciprofloxacin. MIC testing revealed that 6h and 6l were 1.5 times as effective than ciprofloxacin against S. aureus. Compounds 6h and 6l had MBC values of 28 and 33 nM for S. aureus, compared to Ciprofloxacin’s 45 nM, indicating that they are more potent bactericidal agents. The MIC values for compounds 6c, 6e, 6h, 6j, and 6l against A. flavus were between 14.50 and 19.50 µM, while the MIC value for fluconazole was 11.50 µM. Also, the studied compounds had MIC values between 18.20 and 22.90 µM against C. albicans, while Fluconazole had a MIC value of 17.50 µM. Compound 6h showed a MIC value of 1.70 µM against the clinical strain S. aureus (ATCC 43300) (MRSA), making it an effective antibacterial agent. Compounds 6h, 6j, and 6l inhibited E. coli DNA gyrase with IC50 values of 79, 117, and 87 nM, respectively, compared to the reference novobiocin (IC50 = 170 nM). Additionally, compounds 6h and 6l, the most potent E. coli gyrase inhibitors, showed encouraging results on DHFR. Compounds 6h and 6l exhibit IC50 values of 3.80 µM and 4.25 µM, respectively. These values are significantly lower and hence more effective than Trimethoprim’s IC50 of 5.20 µM.

Identification of novel DNA Gyrase inhibitor by combined Pharmacophore modeling, QSAR analysis, Molecular docking, Molecular dynamics, ADMET and DFT approaches

DNA gyrase, an ATP-dependent enzyme, plays a critical role in DNA replication, transcription, and recombination in Mycobacterium tuberculosis (MTB). While fluoroquinolones are effective antibacterial agents targeting DNA gyrase, their clinical use is often limited due to side effects and the emergence of bacterial resistance. In this study, we developed a quantitative structure-activity relationship (QSAR) model to predict the anti-tubercular activity of Quinoline-Aminopiperidine derivatives targeting the DNA gyrase enzyme, using a dataset of 48 compounds obtained from the literature. The QSAR model was validated using both internal and external validation metrics. Model 4, the best predictive model, demonstrated a strong fit with an R² of 0.8393, an adjusted R² (R²adj) of 0.8010, and a lack of fit (LOF) parameter of 0.0626. The QSAR results revealed that DNA gyrase inhibition is significantly influenced by factors such as partition coefficient, molecular flexibility, hydrogen bonding potential, and the presence of fluorine atoms. Twelve quinoline-aminopiperidine derivatives were designed, and their anti-tubercular activity was predicted using QSAR model-4. These compounds were further assessed for pharmacokinetic properties, toxicity, and binding affinity to DNA gyrase. Pharmacophore modeling was also performed and validated using MOE software. The final pharmacophore model includes the features of two aromatic hydrophobic features, one hydrogen bond acceptor, and one hydrogen bond donor. The results indicated that designed compounds QA-3 and dataset compounds C-34 exhibit favorable drug-likeness properties. Molecular dynamics simulations confirmed the stable binding of compounds QA-3 and C-34 to the DNA gyrase protein, highlighting their potential as promising anti-tubercular agents. The developed QSAR Model-4 will facilitate the prediction of anti-tubercular activity in Quinoline-Aminopiperidine derivatives.

Revolutionizing Quinolone Development for DNA Gyrase Targeting; Discovering the Promising Approach to Fighting Microbial Infections

Abstract: DNA gyrase is a type II topoisomerase enzyme that can cause negative supercoiling in DNA by using the energy produced by ATP hydrolysis. There are two main types of topoi-somerases: type I and type II. Type I enzymes cut a single strand of DNA and are further clas-sified as type IA if they connect to a 5′ phosphate of DNA, or type IB if they link to a 3′ phos-phate. Type II topoisomerases break both strands, creating a staggered double-strand break. Antimicrobial resistance is a major concern for the global healthcare system. Resistance is the ability of microorganisms to neutralize and withstand antimicrobial drugs previously used to treat microbial infections. Some known classes of DNA gyrase inhibitors are coumarins, cyclo-thialidines, and quinolones. Antimicrobial medicines such as quinolones have been widely used to treat microbiological diseases. However, the increased use of quinolones has led to the emer-gence of quinolone-resistant bacteria, which poses a serious risk to public health. Microorgan-isms can cause resistance due to changes in the target enzymes, DNA gyrase, and topoisomerase IV, which are responsible for transcription and DNA replication. Additionally, differences in drug entry and efflux may also play a role in resistance. Plasmids that produce the Qnr protein can mediate resistance to quinolones by protecting the quinolone targets from inhibition. This review aims to revolutionize the discovery of quinolone-based antibiotics, specifically targeting DNA gyrase, a critical enzyme in bacterial DNA replication, to enhance the efficacy and spec-ificity of anti-microbail agents against microbial infections.

Insights into antibacterial design: Computational modeling of eugenol derivatives targeting DNA gyrase

The rise of antibiotic resistance underscores the urgent need for novel antibacterial agents. DNA gyrase, an essential enzyme involved in bacterial DNA replication, is a promising target for antibacterial therapy. Computational approaches offer a cost-effective means to design and screen potential inhibitors, such as eugenol derivatives. This study aims to computationally design eugenol derivatives as potential antibacterial agents targeting DNA gyrase, assess their binding affinities, evaluate physicochemical properties, and toxicity, and select lead compounds for further investigation. Molecular docking simulations were conducted to investigate the binding affinities of eugenol derivatives and controls to DNA gyrase. Physicochemical properties and toxicity assessments of eugenol were evaluated. Lead compounds were selected based on drug likeness, toxicity, and binding affinity. Molecular docking studies revealed varying binding affinities of eugenol derivatives to DNA gyrase, with lead compounds exhibiting superior affinity compared to eugenol. Physicochemical properties indicated moderate lipophilicity and low aqueous solubility for eugenol. Toxicity assessment revealed mutagenicity and tumorigenicity. De novo compound synthesis generated 244 novel compounds, with 44 selected based on drug-likeness, toxicity, and binding affinity as lead candidates. These findings provide valuable insights for the development of novel antibacterial agents targeting DNA gyrase, with implications for combating antibiotic resistance.

Synthesis and Molecular Docking Study of Some New Thiazole-coumarin Molecular Hybrids as Antibacterial Agents.

The emergence of drug-resistant bacteria and multidrug-resistant diseases, both of which are associated with high mortality, has posed a serious global health issue. Thiazoles and coumarins were reported as antimicrobial agents. This research paper aims to describe the synthesis of some novel thiazole derivatives bear-ing a coumarin residue as antibacterial agents Methods: The thiazole - coumarin hybrids were synthesized starting from the condensation of 3-acetyl coumarin (1) hydrazine carbothioamide (2) or thisemicarbazide then reacting the resulting products with different p-substituted phenacyl bromides (4a-e), hydrazonoyl chlorides (8a-e), and (11). In vitro antibacterial activity was studied in this work. In addition, molecular docking studies for the new compounds have also been carried out to investigate the binding mode of actions against the target DNA gyrase B. Some of the newly synthesized compounds such as compounds 10b, 7, and 6b showed pronounced activities against Gram (+ve) and Gram (-ve) bacteria compared to a reference antibacterial agent. Compounds 10b, 7, and 6b exhibited the best binding affinity against the target. We could obtain a series of precious hitherto unknown thiazole derivatives with varied antibacterial activities from cheap laboratory-available starting material following rather simple environmentally friendly techniques avoiding the use of hazardous or heavy metal-containing catalysts.

Design, Docking, Synthesis, and In vitro Evaluation of Potent Anti-tubercular Agents Targeting DNA Gyrase

Background: Tuberculosis caused by Mycobacterium tuberculosis has been reported to infect about two-third of the global population and to continuously develop multidrug resistance. DNA gyrase, a type II topoisomerase, is a promising target of the quinolone class of drugs in the treatment of tuberculosis. Objective: The present study is focused on the design and synthesis of newer nitrogen heterocyclics containing indole, n-methyl piperazine, piperidine, and pyrrolidine ring structures. Methods: Initially designed compounds were evaluated for their affinity to the DNA gyrase target. The molecular docking performed using FlexX indicated compounds IIb5 (1-(R)-(4-hydroxyphenyl)(4- methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)urea and IIc5 ((1-(R)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin- 1-yl)methyl) thiourea to exhibit promising binding affinity (dock score of -15.01 and -13.77) respectively when compared to the reference MFX moxifloxacin (dock score -4.40) with the target 5BS8 (DNA gyrase). Further, the best 10 compounds were synthesized by one-pot synthesis employing the reaction of indole/N-methyl piperazine/piperidine/pyrrolidine with N-substituted benzaldehydes in the presence of acetamide/urea/thiourea to afford the compounds in 54.60% to 85.47% yield. The synthesized compounds were suitably characterized using chromatographic and spectroscopic tools. Results: In the microplate Alamar Blue assay (MABA), compounds IIb1, IIIc2, IIIb1, and IIb5 exhibited good minimum inhibitory concentrations of 1.6 μg/mL, 3.12 μg/mL, and 12.5 μg/mL, respectively, when compared to the standard rifampicin with 0.8 μg/mL inhibitory concentration. The MTB gyrase supercoiling assay performed using Mycobacterium tuberculosis gyrase supercoiling assay kit demonstrated compound IIb5 at a concentration of 300 μg/mL to show gyrase inhibition in comparison to MFX at 60 μg/mL. In the MTT assay performed using the human breast cancer cell line MCF-7, compounds IIc2, IIb5, and IIb1 showed IC50 values of 2.57 μM, 12.54 μM, and 12.75 μM, respectively, compared to doxorubicin (1.10 μM) at 7-48 hrs and 72 hrs of the study. Conclusion: Based on these observations, N-methyl piperazine class of compounds can serve as a lead/pharmacophore for the rational design of potent molecules against MTB gyrase to combat the growing issue of MDR-TB.

Synthesis and computational studies of new pyridine, pyrazole, pyran, and pyranopyrimidine-based derivatives of potential antimicrobial activity as DNA gyrase and topoisomerase IV inhibitors

In this study, new derivatives based on pyridine, pyrazole, pyran, and pyranopyrimidine scaffolds 5–14 were designed and synthesized. The newly synthesized compounds were characterized using microanalytical and spectral data. Using amoxicillin and amphotericin B, two common antibacterial and antifungal medications, respectively, the antimicrobial activity of the new compounds was assessed against a variety of strains of both Gram-positive and Gram-negative bacteria as well as fungal infections. The most promising activity was achieved by pyridine-based derivatives 5, 7a, and 7b, which exhibited MIC values ranging from 0.95 to 18.04 µM against the examined bacterial strains and ranging from 4.65 to 33.16 µM against the examined fungal strains. The later derivatives were also evaluated as E. coli DNA gyrase B/topoisomerase IV inhibitors in comparison with novobiocin as a standard drug. Although the assessed candidates 5, 7a, and 7b exhibited a promising suppression impact against E. coli DNA gyrase B (IC50 = 3.11 ± 0.14, 3.85 ± 0.20, and 4.05 ± 0.10, respectively, IC50 novobiocin= 3.64 ± 0.10 µM), they showed detectable less suppression impact against Topoisomerase IV than that of the reference drug with IC50 values of 19.72 ± 1.00, 79.33 ± 0.25, 85.14 ± 0.10, and 13.42 ± 0.05 µM, respectively. Additionally, the safety profiles of 5, 7a, and 7b against WI38 cells were significantly superior to that of novobiocin (IC50 = 138 ± 0.33, 170 ± 0.40, 163.3 ± 0.17, and 86.2 ± 0.03 µM, respectively).Lastly, molecular docking was used to examine the most active derivatives 5, 7a, and 7b's binding capacity to the target DNA gyrase B/topoisomerase IV. The molecules exhibited various H-interactions with the amino acid residues Asp73, Arg76, and Val71 in E. coli DNA gyrase, where compound 5 exhibited H-bonding with the Asp1069 side chain of E. coli Topoisomerase IV. Additional in silico ADMET studies were conducted to represent their oral bioavailability and drug-likeness characteristics.

Navigating fluoroquinolone resistance in Gram-negative bacteria: a comprehensive evaluation.

Since the introduction of quinolone and fluoroquinolone antibiotics to treat bacterial infections in the 1960s, there has been a pronounced increase in the number of bacterial species that have developed resistance to fluoroquinolone treatment. In 2017, the World Health Organization established a priority list of the most critical Gram-negative resistant pathogens. These included Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. In the last three decades, investigations into the mechanisms of fluoroquinolone resistance have revealed that mutations in the target enzymes of fluoroquinolones, DNA gyrase or topoisomerase IV, are the most prevalent mechanism conferring high levels of resistance. Alterations to porins and efflux pumps that facilitate fluoroquinolone permeation and extrusion across the bacterial cell membrane also contribute to the development of resistance. However, there is a growing observation of novel mutants with newer generations of fluoroquinolones, highlighting the need for novel treatments. Currently, steady progress has been made in the development of novel antimicrobial agents that target DNA gyrase or topoisomerase IV through different avenues than current fluoroquinolones to prevent target-mediated resistance. Therefore, an updated review of the current understanding of fluoroquinolone resistance within the literature is imperative to aid in future investigations.

Discovery of new Schiff bases of the disalicylic acid scaffold as DNA gyrase and topoisomerase IV inhibitors endowed with antibacterial properties.

DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids (5a-k) to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets 5f-k exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound 5h demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060μg/mL against S. aureus, E. coli, and P. aeruginosa. 5h had a MIC value of 0.050μg/mL against B. subtilis, which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives 5f, 5h, 5i, and 5k against E. coli DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on E. coli DNA gyrase, with IC50 values ranging from 92 to 112nM. These results indicate that 5f, 5h, 5i, and 5k are more effective than the reference novobiocin, which had an IC50 value of 170nM. Compounds 5f, 5h, 5i, and 5k were subjected to additional assessment against E. coli topoisomerase IV. Compounds 5h and 5i, which have the highest efficacy in inhibiting E. coli gyrase, also demonstrated promising effects on topoisomerase IV. Compounds 5h and 5i exhibit IC50 values of 3.50µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin's IC50 value of 11µM. Docking studies demonstrate the potential of compound 5h as an effective dual inhibitor against E. coli DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.

Comparative In Vitro Killing by Pradofloxacin in Comparison to Ceftiofur, Enrofloxacin, Florfenicol, Marbofloxacin, Tildipirosin, Tilmicosin and Tulathromycin against Bovine Respiratory Bacterial Pathogens

Pradofloxacin is the newest of the veterinary fluoroquinolones to be approved for use in animals—initially companion animals and most recently food animals. It has a broad spectrum of in vitro activity, working actively against Gram-positive/negative, atypical and some anaerobic microorganisms. It simultaneously targets DNA gyrase (topoisomerase type II) and topoisomerase type IV, suggesting a lower propensity to select for antimicrobial resistance. The purpose of this study was to determine the rate and extent of bacterial killing by pradofloxacin against bovine strains of Mannheimia haemolytica and Pasteurella multocida, in comparison with several other agents (ceftiofur, enrofloxacin, florfenicol, marbofloxacin, tildipirosin, tilmicosin and tulathromycin) using four clinically relevant drug concentrations: minimum inhibitory and mutant prevention drug concentration, maximum serum and maximum tissue drug concentrations. At the maximum serum and tissue drug concentrations, pradofloxacin killed 99.99% of M. haemolytica cells following 5 min of drug exposure (versus growth to 76% kill rate for the other agents) and 94.1–98.6% of P. multocida following 60–120 min of drug exposure (versus growth to 98.6% kill rate for the other agents). Statistically significant differences in kill rates were seen between the various drugs tested depending on drug concentration and time of sampling after drug exposure.

Novel Thiazole Derivatives Containing Imidazole and Furan Scaffold: Design, Synthesis, Molecular Docking, Antibacterial, and Antioxidant Evaluation.

Carbothioamides 3a,b were generated in high yield by reacting furan imidazolyl ketone 1 with N-arylthiosemicarbazide in EtOH with a catalytic amount of conc. HCl. The reaction of carbothioamides 3a,b with hydrazonyl chlorides 4a-c in EtOH with triethylamine at reflux produced 1,3-thiazole derivatives 6a-f. In a different approach, the 1,3-thiazole derivatives 6b and 6e were produced by reacting 3a and 3b with chloroacetone to afford 8a and 8b, respectively, followed by diazotization with 4-methylbenzenediazonium chloride. The thiourea derivatives 3a and 3b then reacted with ethyl chloroacetate in ethanol with AcONa at reflux to give the thiazolidinone derivatives 10a and 10b. The produced compounds were tested for antioxidant and antibacterial properties. Using phosphomolybdate, promising thiazoles 3a and 6a showed the best antioxidant activities at 1962.48 and 2007.67 µgAAE/g dry samples, respectively. Thiazoles 3a and 8a had the highest antibacterial activity against S. aureus and E. coli with 28, 25 and 27, 28 mm, respectively. Thiazoles 3a and 6d had the best activity against C. albicans with 26 mm and 37 mm, respectively. Thiazole 6c had the highest activity against A. niger, surpassing cyclohexamide. Most compounds demonstrated lower MIC values than neomycin against E. coli, S. aureus and C. albicans. A molecular docking study examined how antimicrobial compounds interact with DNA gyrase B crystal structures. The study found that all of the compounds had good binding energy to the enzymes and reacted similarly to the native inhibitor with the target DNA gyrase B enzymes' key amino acids.

Molecular docking, ADME-Tox, DFT and molecular dynamics simulation of butyroyl glucopyranoside derivatives against DNA gyrase inhibitors as antimicrobial agents

The emergence of antibiotic resistance highlights the critical need for novel antimicrobial agents. In this study, we investigated the synthesis of methyl α-D-glucopyranoside (1) analogs (2–6) which play vital roles in bacterial replication, in the context of DNA gyrase inhibitors. The unimolar one-step butyroylation of glucopyranoside furnished the 6-O-butyroyl derivative, which was further converted into five newer 6-O-butyroyl-2,3,4-tri-acyl-α-D-glucopyranoside analogs. The newly synthesized chemical structures were determined through physicochemical, elemental, and spectroscopic data. In vitro studies against bacteria and fungi with PASS (activity spectra for substances) prediction showed excellent antimicrobial activity of these glucopyranoside analogs. The cytotoxicity assessment indicated that the compounds exhibited less toxicity. In-depth molecular docking studies were carried out to elucidate the mechanism of action, binding energies, and interaction profiles of the synthesized compounds targeting gyrase. Additionally, a reference molecule, 4-methyl-5-[3-(methylsulfanyl)-1H-pyrazol-5-yl]-2-thiophen-2-yl-1,3-thiazole, was docked into the gyrase receptor to evaluate the inhibitory potential of the synthesized compounds. Moreover, a 100 ns molecular dynamics simulation process was performed to monitor the behavior of the complex structure, and a stable conformation and binding mode were found in the stimulating environment of the compounds. Pharmacokinetic predictions were investigated to evaluate the absorption, distribution, metabolism and toxicity of these compounds, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico. In summary, an integrated computational approach combining molecular docking, ADME-Tox assessment, DFT calculations, and molecular dynamics simulations highlights the promise of these derivatives as candidates for the development of new antimicrobial agents targeting DNA gyrase.

Targeted repression of topA by CRISPRi reveals a critical function for balanced DNA topoisomerase I activity in the Chlamydia trachomatis developmental cycle.

Chlamydia trachomatis is an obligate intracellular bacterium that is responsible for the most prevalent bacterial sexually transmitted infection. Changes in DNA topology in this pathogen have been linked to its pathogenicity-associated developmental cycle. Here, evidence is provided that the balanced activity of DNA topoisomerases contributes to controlling Chlamydia developmental processes. Utilizing catalytically inactivated Cas12 (dCas12)-based clustered regularly interspaced short palindromic repeats interference (CRISPRi) technology, we demonstrate targeted knockdown of chromosomal topA transcription in C. trachomatis without detected toxicity of dCas12. Repression of topA impaired the developmental cycle of C. trachomatis mostly through disruption of its differentiation from a replicative form to an infectious form. Consistent with this, expression of late developmental genes of C. trachomatis was downregulated, while early genes maintained their expression. Importantly, the developmental defect associated with topA knockdown was rescued by overexpressing topA at an appropriate degree and time, directly linking the growth patterns to the levels of topA expression. Interestingly, topA knockdown had effects on DNA gyrase expression, indicating a potential compensatory mechanism for survival to offset TopA deficiency. C. trachomatis with topA knocked down displayed hypersensitivity to moxifloxacin that targets DNA gyrase in comparison with the wild type. These data underscore the requirement of integrated topoisomerase actions to support the essential developmental and transcriptional processes of C. trachomatis.IMPORTANCEWe used genetic and chemical tools to demonstrate the relationship of topoisomerase activities and their obligatory role for the chlamydial developmental cycle. Successfully targeting the essential gene topA with a CRISPRi approach, using dCas12, in C. trachomatis indicates that this method will facilitate the characterization of the essential genome. These findings have an important impact on our understanding of the mechanisms by which well-balanced topoisomerase functions in adaptation of C. trachomatis to unfavorable growth conditions imposed by antibiotics.

In silico analysis of luteolin derivatives as antibacterial agents targeting DNA gyrase and CTX-M-15 extended-spectrum β-lactamase of Escherichia coli.

Luteolin exhibited antibacterial activity against Escherichia coli and its chemical structure similar to that of ciprofloxacin (CPF) which works by inhibiting DNA gyrase. Filtrate from passion fruit extract containing luteolin and its derivatives could inhibit extended-spectrum β-lactamase (ESBL)-producing E. coli. Antibacterial compounds that can also inhibit ESBL will be valuable compounds to overcome the problem of resistant bacteria. This study aimed to ensure the potency of luteolin and luteolin derivatives targeting DNA gyrase and ESBL by in silico approach. Docking simulation of ligands L1-L14 was performed using AutoDock Vina, and pharmacokinetics and toxicity (absorption, distribution, metabolism, excretion, and toxicity) profiles were predicted by pKCSM online. The docking result revealed higher binding affinity on DNA gyrase (PDB.1KZN) of 12 luteolin derivatives (energy <-7.6 kcal/mol) compared to CPF and higher affinity (energy <-6.27 kcal/mol) of all compounds than clavulanic acid against ESBL CTX-M-15 (PDB.4HBU). The compounds could be absorbed through the human intestine moderately, which showed low permeability to blood-brain barrier, nontoxic and nonhepatotoxic. The most active luteolin glycoside (L6) is capable to inhibit DNA gyrase and ESBL from E. coli which provided the potential against resistant bacteria and was promoted as lead compounds to be developed further.

Synthesis and Biological Evaluation of Diphenyl Ether‐Linked Quinolone Derivatives as Antibacterial Agents

AbstractThe increase in the prevalence of multi‐drug‐resistant bacteria poses a significant healthcare challenge. The urgent need to combat the resistant microbes necessitates discovering new antibacterial agents capable of circumventing the existing resistance mechanisms. Targeting DNA gyrase by suitably modifying the fluoroquinolones can lead to antibiotics with better activity and lower incidence of resistance. The substituted diphenyl ethers like triclosan are known to have potent antibacterial activity. In the current study, the hybridisation of diphenyl ether moiety with fluoroquinolones led to the design and synthesis of new compounds with potent inhibitory activity against staphylococcus aureus with MIC 0.5–64 μg/mL and moderately active against mycobacteria with MIC 2–64 μg/mL. The compounds are non‐toxic to Vero cells with a selectivity index &gt;10 to 200. The compounds also inhibited the resistant strains of S. aureus with a MIC ranging from 0.5–64 μg/mL. The synthesised compounds also exhibited potent anti‐biofilm activity against S. aureus. Furthermore, the DNA supercoiling assay revealed the compounds 7 i, 7 o, 7 p and 7 q showed concentration‐dependant DNA‐Gyrase inhibition at 1 μg/mL.

Synthesis, spectroscopic elucidation, density functional theory calculation, and molecular docking studies of a novel series of tetradentate macrocyclic Schiff base ligands and their Zn(II) complexes and investigations of their antimicrobial, anti‐inflammatory, and anticancer activities

In the present work, novel Schiff base macrocyclic Zn(II) complexes [Zn(N8O4MacL1)Cl2–Zn(N8O4MacL3)Cl2] were synthesized by the reaction of ZnCl2 and macrocyclic ligands (N8O4MacL1–N8O4MacL3) derived from the condensation of ligand (L) and dicarboxylic acids [HOOC‐(CH2)n‐COOH]. The structural confirmation of the newly synthesized compounds was accomplished through various analytical techniques, including elemental analysis, infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), UV–visible spectroscopy, and powder X‐ray diffraction (XRD) studies. The spectral data provided evidence that the macrocyclic ligands acted as tetradentate ligands, forming coordination bonds with Zn(II) ions through the nitrogen atom of the imine (&gt;C=N) group. The coordination complexes exhibited an octahedral geometry around the zinc ion, with two chloro groups covalently attached. Density functional theory (DFT) studies of the synthesized Schiff base macrocyclic compounds were carried out to determine their structural and electronic properties. The antimicrobial potential of the macrocyclic compounds was examined against a panel of pathogenic microbes, including four bacterial strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Xanthomonas campestris) and two fungal strains (Fusarium oxysporum and Candida albicans). Then, the newly synthesized Schiff based macrocyclic compounds were evaluated for their anti‐inflammatory activity using an egg albumin method. The synthesized compounds were subjected to further evaluation to assess their potential as anticancer agents against MCF‐7 (human breast adenocarcinoma cell line), HCT‐116 (human colon cancer cell line), and A549 (human alveolar adenocarcinoma epithelial cell line). In addition, molecular docking studies were conducted to explore the potential interactions between the synthesized compounds and the target proteins VEGFR2 (PDB ID 1YWN), EGFR (PDB ID 1M17), and DNA gyrase B (PDB ID 4URO). It was found that there was a high correlation between the experimental results and the docking calculations.

Phytochemical analysis and antibacterial activity of traditional plants for the inhibition of DNA gyrase

Introduction and Aim: DNA gyrase is a class of Type II Topoisomerases that plays an important role in bacterial viability. It is found in all bacteria and is involved in replication, repair, recombination, and DNA transcription. Negative supercoiling of bacterial DNA by DNA gyr B is essential in replication which further influences all the metabolic activities. Staphylococcus aureus (ATCC 25923) is one of the pathogens that can modify its genome easily under multidrug resistance. In this study, the activity of medicinal compounds to inhibit DNA gyrB is explored. Plant species Solanum nigrum, Vitex negundo, and Euphorbia hirta were studied for the potential plant-based molecules. The compounds alkaloids, glycosides, flavonoids, and terpenoids were considered to have high-potential targets. The study focuses on DNA gyrase as a target and shows insights into future drug development. The research focuses on the discovery of novel plant-based therapeutic compounds to target DNA gyrase B activity. Methods and Materials: Phytochemical screening was performed to study the medication options that could inhibit DNA gyrB. Phytochemicals were determined using GC-MS. Results: Utilizing GC MS and FT-IR analysis, the phytochemical constituents of Solanum nigrum, Vitex negundo, and Euphorbia hirta were discovered. It will be simpler to do a follow-up study on discovering bioactive compounds and evaluating their effectiveness in inhibiting DNA gyrB with the help of this preliminary data from the analytical procedures. Conclusion: There are countless applications for the phytochemicals that medicinal plants produce. Staphylococcus aureus will be stopped by DNA gyrB inhibition. The study employs DNA gyrase as its target and provides information on potential therapeutic targets. The goal of the study is to identify innovative plant-based medicinal molecules that specifically target DNA gyrase B activity.

BCp12/PLA combination: A novel antibacterial agent targeting Mur family, DNA gyrase and DHFR

The combination of natural antimicrobial peptide BCp12/phenyllatic acid (BCp12/PLA) presents a more efficient antibacterial effect, but its antibacterial mechanism remains unclear. This study studied the synergistic antibacterial mechanism of BCp12 and PLA against S. aureus. The results demonstrated that the BCp12/PLA combination presented a synergistic antibacterial effect against S. aureus, with a fractional inhibitory concentration of 0.05. Furthermore, flow cytometry and scanning electron microscope analysis revealed that BCp12 and PLA synergistically promoted cell membrane disruption compared with the group treated only with one compound, inducing structural cell damage and cytoplasmic leakage. In addition, fluorescence spectroscopy analysis suggested that BCp12 and PLA synergistically influenced genomic DNA. BCp12 and PLA targeted enzymes related to peptidoglycan and DNA synthesis and interacted by hydrogen bonding and hydrophobic interactions with mur enzymes (murC, murD, murE, murF, and murG), dihydrofolate reductase, and DNA gyrase. Additionally, the combined treatment successfully inhibited microbial reproduction in the storage of pasteurized milk, indicating that the combination of BCp12 and PLA can be used as a new preservative strategy in food systems. Overall, this study could provide potential strategies for preventing and controlling foodborne pathogens.

New Benzopyrrole Derivatives: Synthesis and Appraisal of Their Potential as Antimicrobial Agents.

A series of twenty compounds (23-42) were synthesized and characterized by spectral studies in order to explore newer antimicrobial compounds. The majority of the synthesized compounds reported significant antimicrobial properties against various pathogenic bacterial and fungal strains with the help of tube dilution method. Significant activities (MIC ranging from 3.9 to 15.62 μg/ml) have been shown against Gram-negative and Gram-positive bacteria with. In contrast, moderate to outstanding antibacterial activity was reported versus Gram-negative bacteria such as E. coli and P. aeruginosa along with Gram-positive bacteria such as S. aureus and B. subtilis. While antifungal activity was moderate to excellent against two fungus strains (Candida tropicalis, Candida glabrata). Compounds 25 and 34 had the utmost activity versus Gram-positive and Gram-negative bacteria too. The antifungal activity of compound 35 was comparable to that of standard. In-silico Molecular docking evaluations were performed for antibacterial and antifungal activities against the target DNA gyrase A (PDB: 1AB4) and 14 alpha-sterol demethylase enzyme (PDB: 1EA1), respectively. The dock score for typicals compounds for antibacterial and antifungal activity were -4.733 and -9.4, respectively. The three-dimensional QSAR examination was carried out by multiple linear regression (SA-MLR) with good predictive power (r2=0.9105, q2=0.8011). Establishment of several interactions between the ligand 25 and 34 and the active site of residue of both receptors, enable the ligand 25 and 34 to be fit well in the pocket of the active site, as seen in Molecular dynamics simulations analysis. Thus, data suggest that these ligands could be further explored as potential precursors to develop antimicrobial drugs.