Bacterial DNA Gyrase Research Articles

Identification of 4-diphenylamino 3-iodo coumarin as a potent inhibitor of DNA gyrase B of S. aureus

A necessity of therapeutics against antibiotic-resistant bacteria has led to a search for novel antibacterial compounds. The strategy to isolate compounds from non-microbial sources is the key to prevent antibiotic resistance. Here, we report isolation and characterization of an antibacterial coumarin derivative, 4-diphenylamino 3-iodo coumarin (4-DPA3IC) from a traditional drug formulation. The compound elicited high activity against MDR strains of S. aureus. Targets were identified through computational methods encompassing modules of Schrodinger 10.4. The 4-DPA3IC targeted S. aureus DNA gyrase enzyme B subunit. Amino acid residues and interactions involved here are totally different from those of novobiocin and clorobiocin. The validation was done by in vitro DNA gyrase supercoiling inhibition assay. This study proved 4-DPA3IC could potentially act against novobiocin and cholorbiocin resistant strains of S. aureus. Thus, the 4-DPA3IC is a unique inhibitor of bacterial DNA gyrase due to its plant origin as compared to other reported inhibitors.

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

Phytofabricated silver nanoparticles: Discovery of antibacterial targets against diabetic foot ulcer derived resistant bacterial isolates

The present study selected the predominant multi antibiotic-resistant diabetic foot ulcer (DFU) derived bacterial isolates such as Pseudomonas aeruginosa (PA), Escherichia coli (EC), Staphylococcus aureus (SA) and Bacillus subtilis (BS) and evaluated their response against the well-characterized Aerva lanata (AL) reduced multiple phytochemicals fabricated silver nanoparticles (AL-AgNPs). The overnight culture of DFU isolates was processed and subjected to various studies such as antimicrobial activity, growth kinetics, biofilm disruption, reactive oxygen species (ROS), membrane leakage, membrane permeability, and damage and genotoxicity. The molecular docking of AL phytochemicals was also performed with bacterial enzyme DNA gyrase. Interestingly, AL-AgNPs were produced the remarkable antibacterial effect against the resistant DFU isolates, which was closely similar to the effect of AL-AgNPs observed against the reference strains. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of AL-AgNPs against the DFU isolates were found to be 5-15μg/mL and 10-20μg/mL, respectively. The AL-AgNPs were depicted a concentration-dependent growth inhibition of DFU bacterial isolates. The MIC and MBC of AL-AgNPs were effectively destroyed the preformed biofilms of DFU isolates. Furthermore, the MBC of AL-AgNPs was displayed the increased intracellular ROS accumulation, membrane leakage, permeability and damage, and genotoxicity in the DFU isolates. Additionally, the in silico study revealed that the AL phytochemicals were fitted over the binding pocket of the DNA gyrase B subunit. The observed results were confirmed that the negative impacts of the AL-AgNPs at the level of the membrane and intracellular components of DFU isolates.

The complete sequence, annotation and comparative analysis of the Escherichia coli IncFII family plasmid pMccB17, encoding biosynthetic and immunity functions for the antimicrobial peptide microcin B17

Microcin B17 (Mcb17) is a ribosomally synthesized and post-translationally modified peptide (RiPP), produced by Escherichia coli, that inhibits bacterial DNA gyrase in a similar way to quinolones. The Mcb17 operon, consisting of seven genes encoding biosynthetic and immunity/export functions, was originally found on a plasmid, pMccB17. This circular plasmid, previously known as pRYC17, was originally found in Escherichia coli strain LP17, isolated from the intestinal tract of a healthy newborn at Hospital La Paz, Spain and was transferred by conjugation to E. coli K-12 [Baquero et al. (1978) J. Bacteriol. 135: 342]. pMccB17 is a low copy number IncFII plasmid in the same incompatibility group as R100 and R1. Not much is known about this plasmid aside from the facts that it carries the Mcb17 operon, does not possess any conventional antibiotic resistance markers and its size was estimated to be approximately 70 kb. We extracted the plasmid from E. coli K-12 strain RYC1000 [pMccB17] and sequenced it twice using an Illumina short-read method, firstly together with the host bacterial chromosome, then plasmid DNA was purified and sequenced separately. PCR primers were designed to close the single remaining gap via Sanger sequencing. The resulting complete sequence has 83 predicted genes, initially identified by Prokka and subsequently manually reannotated using BLAST. Comparison to other IncFII plasmids shows a large proportion of shared genes, especially in the conjugative plasmid backbone. However, pMccB17 which is a MOBF12 plasmid lacks transposable elements and in addition to the Mcb17 operon, this plasmid carries 25 genes of unknown function.

Discovery of new ATP-competitive inhibitors of human DNA topoisomerase IIα through screening of bacterial topoisomerase inhibitors

Human DNA topoisomerase II is one of the major targets in anticancer therapy, however ATP-competitive inhibitors of this target have not yet reached their full potential. ATPase domain of human DNA topoisomerase II belongs to the GHKL ATPase superfamily and shares a very high 3D structural similarity with other superfamily members, including bacterial topoisomerases. In this work we report the discovery of a new chemotype of ATP-competitive inhibitors of human DNA topoisomerase IIα that were discovered through screening of in-house library of ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV. Systematic screening of this library provided us with 20 hit compounds. 1,2,4-Substituted N-phenylpyrrolamides were selected for a further exploration which resulted in 13 new analogues, including 52 with potent activity in relaxation assay (IC50 = 3.2 µM) and ATPase assay (IC50 = 0.43 µM). Cytotoxic activity of all hits was determined in MCF-7 cancer cell line and the most potent compounds, 16 and 20, showed an IC50 value of 8.7 and 8.2 µM, respectively.

DESIGN, SYNTHESIS OF SCHIFF BASE CIPROPFLOXACIN-VANILLIN DERAVATIVES OF POTENT BACTERIAL DNA GYRASE INHIBITOR

A series of Schiff base ciprofloxacin hydrazones with vanillin analogues were designed and validated for druggability properties by advanced computational tools, from which two shortlisted compounds were synthesized and characterized by different spectral studies. These compounds were used against bacterial DNA gyrase; purposedly attempted in molecular docking studies, the compounds 5h and 5i indicated good binding affinity of -8.2 and -8.5 kcal/mol, respectively. Moreover, in vitro antibacterial activities against uropathogenic bacteria, E. coli, was assessed and the compounds 5h, and 5i had significant inhibitory actions. SAR studies revealed that the presence of the quinolone nucleus, azomethine functional group and vanillyl ester might have shown the response of antibacterial inhibition. Thus, vanillyl esters condensed with ciprofloxacin hydrazone through Schiff base, have more antibacterial inhibitory actions. The recorded antibacterial results were corroborated with docking results.

Synthesis and In Silico Molecular Docking Studies on Substituted Piperic Acid Derivatives as Inhibitors of Bacterial DNA Gyrase

Piperine or piperic acid was isolated from fruits of Piper nigrum and had been reported as pharmacological valuable bioactive constituents. Keeping in view, a series of piperic acid-based N heterocyclic's derivatives were synthesized and evaluated for antibacterial activity. All these prepared ligands were docked to study the molecular interactions and binding affinities against the protein PDB ID: 5 CDP. To meet the real need of newer antibacterials, we designed and synthesized scaffolds with good antibacterial activity. The obtained antibacterials have been validated in terms of ligand-protein interaction and thus prove to build up as good drug candidates. Antibacterial activity of the compounds were carried out against bacterial strains; three Grampositive and three Gram-negative bacterial strains using agar well diffusion method. In silico molecular docking studies were carried out using Glide (grid-based ligand docking) program incorporated in the Schrödinger molecular modeling package by Maestro 11.0. Compounds BC 28, BC 32, and BC 33 exhibits antibacterial activity along with Glide docking score of -8.580, -9.753 kcal/mol, and -8.813 kcal/mol, respectively. Docking studies explained hydrogen bonding, pi-pi, and hydrophobic interactions with amino acid residues which explain the binding affinity of the most docked ligand with protein. In the present study, substituted piperic acid was synthesized and evaluated as antibacterial compared with standard drug ciprofloxacin and results interpret that having nitrogen as heteroatom in the heterocyclic nucleus found to be more potent than the standard drug ciprofloxacin. On comparing, substitution with electron-donating groups generates excellent antibacterial potential against the bacterial strains. It was also proved that having substitution with electron-donating groups on meta and para position with triazoline ring system exhibits greater potential while compounds which have a meta- electron-donating substituent showed lesser activity with thiazole nucleus. In addition, structure-based activities of the prepared analogs were discussed under Structure-Activity Relationship (SAR) section.

Investigating the mechanism of binding of nalidixic acid with deoxyribonucleic acid and serum albumin: a biophysical and molecular docking approaches

Nalidixic acid is a bacterial DNA gyrase inhibitor and the first member of the synthetic quinolone antibiotics. It is used in the treatment of various infectious diseases like urinary tract infections, respiratory infections, sexually transmitted diseases, acute bronchitis, and sinusitis. Interactions studies are of great significance as it will be beneficial for designing new therapeutic molecules with preferable plasma solubility and its efficacy. In this paper, we have aim to ascertain the binding mode of nalidixic acid with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) through various biophysical and in silico method. UV-visible absorption and fluorescence spectroscopic experiments confirmed the formation of a complex between nalidixic acid with ct-DNA. The binding constant is in the range of 103 M−1, indicating the groove binding mode between ct-DNA and nalidixic acid. Groove binding mode was also validated by competitive displacement assay, potassium iodide quenching experiment, circular dichroism, DNA melting studies. In the case of BSA, UV-visible absorption and fluorescence spectroscopic experiments confirmed the formation of a complex between nalidixic acid with BSA. The value of a binding constant in the case of BSA was found to be 1.517 × 105 M−1. The site marker displacement experiment revealed the binding location of nalidixic acid to a site I in BSA. Secondary structural and microenvironmental changes also studied through circular dichroism and three-dimensional fluorescence. Furthermore, the synchronous fluorescence spectra of BSA with nalidixic acid showed that there were changes in the microenvironment around tryptophan residues. In silico molecular docking further confirmed the binding of nalidixic acid to site I in BSA and the minor groove of DNA.Communicated by Ramaswamy H. Sarma

Levonadifloxacin arginine salt to treat acute bacterial skin and skin structure infection due to S. aureus including MRSA.

Acute bacterial skin and skin structure infections (ABSSSIs) are one of the most common types of infections due to methicillin-resistant Staphylococcus aureus (MRSA). The standard of care for ABSSSI includes glycopeptides such as vancomycin, teicoplanin, oxazolidinones and fluoroquinolones, which are potent broad-spectrum antibacterial agents. Unfortunately, due to indiscriminate utilization, resistance to these agents is rising and identification of novel agents is an urgent unmet medical need. In this context, levonadifloxacin (WCK-771) is a novel, hydrate arginine salt of nadifloxacin with improved bactericidal activity against MRSA as well as fluoroquinolone-resistant S. aureus by targeting bacterial DNA supercoiling enzymes DNA gyrase and topoisomerase IV. Levonadifloxacin displays a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria, atypical bacteria, anaerobic bacteria and bioterror pathogens with a very low frequency of mutation. Levonadifloxacin also displays improved activity under low pH biofilm environments. The drug has successfully completed phase I, phase II and phase III clinical trials in India. The U.S. Food and Drug Administration (FDA) granted a Qualified Infectious Disease Product (QIDP) designation to levonadifloxacin for the treatment of MRSA infections in August 2014.

Synthesis, antibacterial activity and docking studies of chloroacetamide derivatives

Structural modification of lead compounds is a great challenge in organic synthesis. Introduction of different functional groups not only modify the structure of starting material but also improve their biological activeness. Small synthetic molecules are favored in spite of the reality that majority of drug molecules derived from natural sources, are in vogue. In the present work, acetamide derivatives were synthesized using chloroacetyl chloride. After synthesizing targeted series of acetamide derivatives these compounds were further modified using different amines including 2-aminobenzene thiol, benzyl amine, benzene 1,4-diamine, 4-amino-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one, 4-aminophenol, hydrazine and 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide. All of these synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR and X-ray crystallography. The compounds were assessed for their anti-bacterial activity using disc diffusion method against Staphylococcus aureus and Escherichia coli. The compounds were found to exhibit comparable activity to the standard drug used. This was further supported by molecular docking studies using bacterial DNA gyrase and Topoisomerase II targets causing bacterial death as they are major bacterial proteins known to be involved in transcription and replication process. Results proved that the compound 2b was the most efficacious antimicrobial compound among the synthesized set of compounds. To tackle the growing drug resistance acetamide based functionalities can be regarded as the active lead compounds to target different drug resistance microorganism.

Design, synthesis and biological evaluation of novel DNA gyrase inhibitors and their siderophore mimic conjugates

Bacterial DNA gyrase is an important target for the development of novel antibacterial drugs, which are urgently needed because of high level of antibiotic resistance worldwide. We designed and synthesized new 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase B inhibitors and their conjugates with siderophore mimics, which were introduced to increase the uptake of inhibitors into the bacterial cytoplasm. The most potent conjugate 34 had an IC50 of 58 nM against Escherichia coli DNA gyrase and displayed MIC of 14 µg/mL against E. coli ΔtolC strain. Only minor improvements in the antibacterial activities against wild-type E. coli in low-iron conditions were seen for DNA gyrase inhibitor – siderophore mimic conjugates.

Extensive Structure-Activity Relationship Study of Albicidin's C-Terminal Dipeptidic p-Aminobenzoic Acid Moiety.

Albicidin is a recently described natural product that strongly inhibits bacterial DNA gyrase. The pronounced activity, particularly against Gram‐negative bacteria, turns it into a promising lead structure for an antibacterial drug. Hence, structure–activity relationship studies are key for the in‐depth understanding of structural features/moieties affecting gyrase inhibition, antibacterial activity and overcoming resistance. The 27 newly synthesized albicidins give profound insights into possibilities for variations of the C‐terminus. Furthermore, in the present study, a novel derivative has been identified as overcoming resistance posed by the Klebsiella‐protease AlbD. Structural modifications include, for example, azahistidine replacing the previous instable cyanoalanine as the central amino acid, as well as a triazole amide bond isostere between building blocks D and E.

724. The In Vitro Activity of Gepotidacin and Comparator Agents Against Anaerobic Bacterial Isolates

BackgroundGepotidacin (GSK2140944) is a first in class novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in clinical development for the treatment of gonorrhea and uncomplicated UTI (acute cystitis). Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved therapeutic agent and demonstrates in vitro activity against most target pathogens resistant to established antibacterials, including fluoroquinolones. This study assessed the in vitro activity of gepotidacin and comparators against a collection of 649 Gram-positive and Gram-negative anaerobic bacterial clinical isolates.MethodsA total of 649 clinically significant Gram-negative (333) and Gram-positive (316) anaerobic clinical isolates previously collected and frozen at −70°C were tested. Isolates came from North America (315/48.5%) and Europe (334/51.5%) and were collected between 2000 and 2017. Minimum inhibitory concentrations (MICs) for gepotidacin and 6 comparators were determined by agar dilution (AD) for all isolates, and by both AD and broth microdilution (BMD) for Bacteroides spp. according to CLSI guidelines (CLSI M11-A8). Most Lactobacillus spp. tested in this study require anaerobic conditions for growth and were tested by anaerobic AD.ResultsThe in vitro activity results of gepotidacin and comparators are shown in the table below. The gepotidacin MIC90 for all Gram-negative anaerobic isolates tested in this study was 4 µg/mL and for the comparators tested was as follows: ceftriaxone 512 μg/mL, clindamycin >8 μg/mL, imipenem 0.5 μg/mL, metronidazole 2 μg/mL, moxifloxacin 8 μg/mL and piperacillin–tazobactam 16 μg/mL. Gepotidacin had the lowest MIC90 (2 μg/mL) for the Gram-positive anaerobic isolates compared with the other antibiotics tested, with the exception of metronidazole (MIC90 = 0.5 µg/mL).ConclusionGepotidacin showed in vitro activity against a collection of 649 anaerobic Gram-negative and Gram-positive clinical isolates, with an MIC90 value against all Gram-negative anaerobic isolates of 4 µg/mL, and against all Gram-positive anaerobic isolates of 2 µg/mL. Disclosures All authors: No reported disclosures.

701. Comparison of MIC Results for Gepotidacin by Agar Dilution and Broth Microdilution Methods

BackgroundGepotidacin (GSK2140944) is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in clinical development for the treatment of gonorrhea and uncomplicated UTI (acute cystitis). Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved therapeutic agent and demonstrates in vitro activity against most target pathogens resistant to established antibacterials, including fluoroquinolones. This study tested the equivalency of minimal inhibitory concentrations (MICs) obtained by 2 reference susceptibility testing methods, agar dilution (AD) and broth microdilution (BMD), for gepotidacin against Gram-positive and Gram-negative organisms.MethodsSusceptibility testing for both methods was performed on a total of 733 clinical isolates recovered largely in 2016 from over 120 medical centers worldwide. For N. gonorrhoeae, only the AD method is recommended by CLSI, therefore BMD was performed using Fastidious Broth for comparison purposes. Essential agreement (EA) based on evaluable results was calculated as the number of isolates with MICs within one 2-fold dilution of the reference method divided by the total number of results. Equivalency was defined using the 95% criteria from the FDA’s class II controls document.ResultsThe EA observed for gepotidacin with these 2 methods was 85.8% overall and 98.3% when H. influenzae and N. gonorrhoeae isolates were excluded. Slightly higher gepotidacin MICs were observed when tested by BMD for each of these species/groups; this trend was especially prominent for E. coli and S. pyogenes. Gepotidacin tested against H. influenzae (73.1%) or N. gonorrhoeae (28.6%) species had much lower EAs.ConclusionEquivalency (EA >95%) was established between AD and BMD methods for determining gepotidacin susceptibility results against Staphylococcus spp., Streptococcus spp. and E. coli. However, for N. gonorrhoeae and H. influenzae, equivalency between the 2 methods was not established; therefore, future antimicrobial susceptibility testing for gepotidacin against these organisms should adhere to the methods for which quality control ranges and breakpoints are approved. Disclosures All authors: No reported disclosures.

714. Analysis of the Effect of Urine on the In Vitro Activity of Gepotidacin and Levofloxacin Against Escherichia coli, Staphylococcus epidermidis, and Staphylococcus saprophyticus

BackgroundGepotidacin (GSK2140944) is a first in class novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in clinical development for the treatment of gonorrhea and uncomplicated UTI (acute cystitis). Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved therapeutic agent and demonstrates in vitro activity against most target pathogens resistant to established antibacterials, including fluoroquinolones. This study was undertaken to determine the effect of various urine parameters on the in vitro activity of gepotidacin and a comparative agent, levofloxacin, against a variety of bacteria.MethodsStudy strains were tested according to the reference CLSI broth microdilution method using cation-adjusted Mueller–Hinton broth (CAMHB) and the following method variations: CAMHB with 25%, 50%, and 100% urine (not pH adjusted) and 100% urine (pH adjusted to 7.2–7.4, and 8). Quality control strains were concurrently tested each day.ResultsMIC endpoints in the reference method and in 100% urine were easily determined (i.e., clear buttons of growth up to the first well of no growth). Gepotidacin MIC results are summarized in the table. For E. coli and S. saprophyticus, there was a trend for higher gepotidacin MIC results with the addition of increasing amounts of urine. However, the increase was minimal such that mean dilution differences were ≤ 1.54. Against S. epidermidis, gepotidacin MICs were not significantly impacted by the addition of urine as 100% of urine condition MICs were within ±1 doubling dilution of the reference method MIC. The gepotidacin results for E. coli indicate that the average 1–2 dilution MIC increase observed in the unadjusted 100% pooled urine MIC may be associated with lower pH. A similar increase in levofloxacin MIC results for E. coli were also associated with pH, but at the higher pH of 8.0. In contrast, the increase in MIC observed in both the gepotidacin and levofloxacin S. saprophyticus results in 100% pooled urine do not appear to be a function of pH.ConclusionOverall, the effect of urine on the gepotidacin and levofloxacin MICs was minimal and not inclusive of all strains tested. Disclosures All authors: No reported disclosures.

ANTIBACTERIAL PROPERTY AND MOLECULAR DOCKING STUDIES OF METHANOLIC FUNGAL PHYTOCHEMICALS OF CLAVICEPS PURPUREA INFECTED TO BAJRA (PENNISETUM GLAUCUM) CROP

Objective: The objective of this study is to study the antibacterial activity, minimum inhibitory concentration, preliminary phytochemical studies, molecular docking studies, and high-resolution liquid chromatography mass spectrometer (HR-LCMS) analysis of the methanol fungal extract of Claviceps purpurea. 
 Methods: Mass production of the fungal mat of C. purpurea was established on potato dextrose broth medium. The dried methanol extract of fungus was subjected to HR-LCMS analysis; antibacterial screening of the extract was carried out against pathogenic bacteria. Molecular docking study of HR-LCMS identified compounds was performed by docking with bacterial enzyme DNA gyrase.
 Results: HR-LCMS analysis of methanol extract of C. purpurea fungus shows that the compounds arecoline, benperidol, felbamate, solanidine, and triparanol as the major constituents. The antibacterial screening of methanol extract of fungus against bacterial pathogens showed a significant bactericidal activity against the strains Pseudomonas aeruginosa (14.40±0.04 mm), Xanthomonas campestris (13.60±0.06 mm), Escherichia coli (13.40±0.06 mm), Salmonella Typhi (11.50±0.05 mm), Staphylococcus aureus (11.37±0.04 mm.), and as matched to the standard drug ciprofloxacin. The molecular docking of triparanol against the bacterial enzyme DNA gyrase showed good binding affinity of −6.2 kcal/mol, good drug likeness (7.3767), 2 hydrogen bonds, and hydrophobic interaction with 8 amino acid residues so that triparanol shows good inhibitor as compared to other 4 compounds.
 Conclusion: Methanol fungal extract of C. purpurea showed significant antibacterial activity against pathogenic bacteria. Triparanol is the major compound present in C. purpurea fungus which showed good inhibitory activity against bacterial enzyme DNA gyrase. The methanol extract of C. purpurea fungus displayed a good antibacterial drug.

Molecular docking, Hirshfeld surface analysis and spectroscopic investigations of 1-(adamantan-1-yl)-3-(4-fluorophenyl)thiourea: A potential bioactive agent

In this study, the optimized molecular structure, Hirshfeld surface analysis, vibrational frequencies and corresponding vibrational modes of a potential bioactive agent namely; 1-(adamantan-1-yl)-3-(4-fluorophenyl)thiourea were studied experimentally and theoretically. The theoretical calculations of the title compound were carried out using the density functional theory (DFT/B3LYP and DFT/M06-2X) quantum mechanical method with 6-311++G(d,p) basis set and Gaussian 09W program. The vibrational assignments of the title compound were obtained using VEDA 4 program by %10 precision with the help of potential energy distributions (PED). The experimental (FT-IR and Laser-Raman) spectra were recorded in solid phase at 4000–400 cm−1 (FT-IR) and 4000–100 cm−1 (Laser-Raman). Additionally, the experimental and theoretical 1H and 13C NMR chemical shifts in DMSO‑d6 and UV–Vis. Spectral analysis in DMF were studied theoretically and experimentally. The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) analyses were performed. The molecular docking studies of the title compound revealed that it may exhibit antibacterial activity via inhibition of bacterial DNA gyrase PDB: 3U2D enzyme.

Evaluation of Antimicrobial Profile of Some Novel 1, 3, 4-Oxadiazole Derivatives Followed by Molecular Docking Against 3G7E Bacterial DNA Gyrase

The main aim and objective of the present research work was the design, synthesis, spectral characterization and evaluation of in vitro antimicrobial profile of some novel oxadiazole derivatives followed by molecular docking studies against bacterial DNA gyrase. The molecular structures of the synthesized compounds were assigned by IR, NMR and Mass spectral analysis. Molecular docking studies were carried out by AUTO DOCK programme. The in vitro antibacterial and antifungal activities were done by paper disk diffusion and agar streak dilution technique. In silico molecular docking studies the binding energy of synthesized compounds (AB1-AB8) were found to be -7.66, -7.67, -7.12, -7.12, -6.59, -6.46, -7.35, -5.09 which indicated that the compound had the high binding affinity towards the bacterial DNA gyrase with PDB id 3G7E and inhibit the function topoisomerase in comparison with standard drug ciprofloxacin (-7.44). The preliminary antimicrobial screening displayed that most of the synthesized compounds were executed moderate to good antimicrobial activity against following bacteria: S. aureus (ATCC 9144), B. subtilis (ATCC 6633), S. epidermidis (ATCC 12228), P. Aeruginosa (ATCC27853), E.coli (ATCC25922), V. cholerrae (ATCC14035) and fungi: A. Niger (ATCC 9029), A.flavus (ATCC204304), C. albicans (ATCC10231) and B. dermatitis (ATCC 26199) etc. All the synthesized compounds exhibited moderate to good antibacterial and antifungal activity with an MIC range of 12-37µg/ml. Among these eight synthesized oxadiazole derivatives, compound AB1; AB2 and AB7 were found to be very good antibacterial as well as antifungal potentiality with an MIC range of 13-12 µg/ml; 7-10 µg/ml and 15-18 µg/ml. Keywords: Molecular docking; NMR; disk diffusion; antibacterial; antifungal and MIC etc.

Antimicrobial, antioxidant and cytotoxic evaluation of diazenyl chalcones along with insights to mechanism of interaction by molecular docking studies

BackgroundIn continuation of our work, new diazenyl chalcones scaffolds (C-18 to C-27) were efficiently synthesized from substituted acetophenone azo dyes (A–E) by base catalyzed Claisen–Schmidt condensation with different substituted aromatic/heteroaromatic aldehydes.MethodologyThe synthesized chalcones were assessed for their in vitro antimicrobial potential towards several pathogenic microbial strains by tube dilution method and further evaluated for antioxidant potential by DPPH assay. These derivatives were also assessed for the cytotoxicity towards the human lung cancer cell line (A549) and normal cell line (HEK) by MTT assay. The most active antimicrobial compounds were docked using Schrodinger v18.1 software with the various potential bacterial receptors to explore the mechanism of interaction.ResultsThe derivative C-22 exhibited high antibacterial activity with very low MIC (1.95–3.90 µg ml−1) and MBC (3.90–7.81 µg ml−1) values. The derivatives C-23, C-24 and C-27 have demonstrated good antioxidant potential (IC50 = 7–18 µg ml−1) correlated to the ascorbic acid (IC50 = 4.45 µg ml−1). The derivative C-25 had shown comparable cytotoxicity to camptothecin against A549 cell line. The docking studies predicted the bacterial dihydrofolate reductase (PDB ID: 3SRW) and bacterial DNA gyrase (PDB ID: 4ZVI) as the possible targets for most of the active antimicrobial compounds. These derivatives affirmed their safety by presenting less cytotoxicity towards HEK cells. Further the ADME prediction by qikprop module of the Schrodinger proved that these compounds exhibited drug-like attributes.ConclusionHence, these compounds have shown their potential as lead for future expansion of novel antimicrobial and cytotoxic drugs.

Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies

Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.