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Frontiers in Chemistry 2024DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been...
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 () to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060 μg/mL against , , and . had a MIC value of 0.050 μg/mL against , which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives , , , and against DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on DNA gyrase, with IC values ranging from 92 to 112 nM. These results indicate that , , , and are more effective than the reference novobiocin, which had an IC value of 170 nM. Compounds , , , and were subjected to additional assessment against topoisomerase IV. Compounds and , which have the highest efficacy in inhibiting gyrase, also demonstrated promising effects on topoisomerase IV. Compounds and exhibit IC values of 3.50 µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin's IC value of 11 µM. Docking studies demonstrate the potential of compound as an effective dual inhibitor against DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.
PubMed: 38911996
DOI: 10.3389/fchem.2024.1419242 -
RSC Advances Jun 2024In this study, nickel selenide (NiSe), Ag/CN-NiSe, and CN/Ag-NiSe nanowires (NWs) were synthesized coprecipitation. The prepared NWs were employed for the degradation...
In this study, nickel selenide (NiSe), Ag/CN-NiSe, and CN/Ag-NiSe nanowires (NWs) were synthesized coprecipitation. The prepared NWs were employed for the degradation of the rhodamine B (RhB) dye in the absence of light using sodium borohydride (NaBH), bactericidal activity against pathogenic () and docking study to investigate the d-alanine ligase (DDl) and deoxyribonucleic acid (DNA) gyrase of . NWs demonstrate a catalytic degradation efficiency of 69.58% toward RhB in a basic medium. The percentage efficacy of the synthesized materials was evaluated as 19.12-42.62% at low and 36.61-49.72% at high concentrations against pathogenic . Molecular docking results suggest that both CN/Ag-doped NiSe and Ag/CN-doped NiSe possess inhibitory activities toward DDl and DNA gyrase of , which coincides with the bactericidal activity. Based on the research outcomes, the synthesized NWs show potential as an effective agent for water purification and resistance to microbial contaminants.
PubMed: 38911830
DOI: 10.1039/d4ra01437e -
Bioorganic & Medicinal Chemistry Jun 2024N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide...
Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study.
N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.
PubMed: 38906068
DOI: 10.1016/j.bmc.2024.117798 -
BMC Veterinary Research Jun 2024The health of calves has a significant impact on the production of cows and livestock. Some desert plants have pharmacological importance, as they can be used to reduce...
The health of calves has a significant impact on the production of cows and livestock. Some desert plants have pharmacological importance, as they can be used to reduce antibiotic resistance. Our hypothesis is designed to detect Virulent- Multidrug-Resistant and Extended- spectrum Beta- lactamase Enterobacteriaceae (Virulent-MDR-ESBL Enterobacteriaceae and to determine whether Moringa oleifera has antibacterial activity against the detected isolates. A total of 39 Enterobacteriaceae isolates from 28 diarrheic samples were collected from calves aged between 20 days and 20 months from 3 different flocks in North Sinai, Sahl-Eltina region, Egypt. E.coli 46% (18/39), O157 13% (5/39), Klebsiella pneumoniae 41% (16/39). MDR members accounted for 87%, while ESBL isolates accounted for 43%. The antibacterial activity is represented by microdilution. Minimum inhibition concentration (MIC) for the methanol extract of Moringa oleifera ranged from 2.5,5,10, and 25mg/ ml among E.coli isolates, and O157 was susceptible to (2.5mg/ ml), Klebsiella pneumoniae isolates were susceptible to (5-50mg/ ml). Analysis of the methanol extract revealed that ferulic acid was the dominant phenolic compound with a concentration of 29,832 parts per million (ppm). In silico docking study expected the active site of ferulic acid to act on the tyrosine bacterial enzyme through Pi-alkyl, Pi-anion, Carbon hydrogen bonds, and extra ionic attractive interactions with copper ions which can stabilize ferulic acid inside the targeted pocket Diverse virulent gene profiles were observed in E. coli. The Shiga toxin-producing Escherichia coli (STEC) was reported in 83% of the isolated E. coli, while the DNA gyrase (gyrA) was harbored in 100% of Klebsiella pneumoniae isolates. Various profiles of antibiotic resistance genes for both E. coli and Klebsiella pneumoniae isolates were distinguished. bla genes were detected in 99% of E. coli and 100% of Klebsiella pneumoniae. Sequence analysis for E. coli strain DRC-North Sinai-Eg was placed in accession numbers (OP955786) for the Shiga toxin 2 gene (Stx2A), (OP997748) and (OP997749) for the Adhesion to host cell gene (Eae). For the hemolysine gene (hylA), the accession number was (OP946183). Klebsiella pneumoniae strain DRC-North Sinai-Eg was placed in (OP946180) for (gyrA). This study has proven the broad range of Moringa oliefera's antibacterial effects in vitro against the virulent-MDR- ESBL E. coli and Klebsiella pneumoniae isolated from North Sinai calves diarrhea. These are congruent with the disability effect on bacterial tyrosinase enzyme through docking study therefore, we recommend the usage of this desert plant as a prospective feed additive, we endorse this as an antibacterial new insight natural source and for the medication of considered pathogens with zoonotic impacts.
Topics: Animals; Cattle; Klebsiella pneumoniae; Moringa oleifera; Diarrhea; Cattle Diseases; Escherichia coli; Microbial Sensitivity Tests; Anti-Bacterial Agents; Plant Extracts; Drug Resistance, Multiple, Bacterial; beta-Lactamases; Egypt; Escherichia coli Infections; Klebsiella Infections; Virulence; Molecular Docking Simulation
PubMed: 38877453
DOI: 10.1186/s12917-024-04088-7 -
Microbiology Spectrum Jun 2024Clorobiocin is a well-known, highly effective inhibitor of DNA gyrase belonging to the aminocoumarin antibiotics. To identify potentially novel derivatives of this...
UNLABELLED
Clorobiocin is a well-known, highly effective inhibitor of DNA gyrase belonging to the aminocoumarin antibiotics. To identify potentially novel derivatives of this natural product, we conducted an untargeted investigation of clorobiocin biosynthesis in the known producer DS 12.976 using LC-MS, molecular networking, and analysis of fragmentation spectra. Previously undescribed clorobiocin derivatives uncovered in this study include bromobiocin, a variant halogenated with bromine instead of chlorine, hydroxylated clorobiocin, carrying an additional hydroxyl group on its 5-methyl-pyrrole 2-carboxyl moiety, and two other derivatives with modifications on their 3-dimethylallyl 4-hydroxybenzoate moieties. Furthermore, we identified several compounds not previously considered clorobiocin pathway products, which provide new insights into the clorobiocin biosynthetic pathway. By supplementing the medium with different concentrations of potassium bromide, we confirmed that the clorobiocin halogenase can utilize bromine instead of chlorine. The reaction, however, is impeded such that non-halogenated clorobiocin derivatives accumulate. Preliminary assays indicate that the antibacterial activity of bromobioin against and efflux-impaired matches that of clorobiocin. Our findings emphasize that yet unexplored compounds can be discovered from established strains and biosynthetic gene clusters by means of metabolomics analysis and highlight the utility of LC-MS-based methods to contribute to unraveling natural product biosynthetic pathways.
IMPORTANCE
The aminocoumarin clorobiocin is a well-known gyrase inhibitor produced by the gram-positive bacterium DS 12.976. To gain a deeper understanding of the biosynthetic pathway of this complex composite of three chemically distinct entities and the product spectrum, we chose a metabolite-centric approach. Employing high-resolution LC-MS analysis, we investigated the pathway products in extracted culture supernatants of the natural producer. Novel pathway products were identified that expand our understanding of three aspects of the biosynthetic pathway, namely the modification of the noviose, transfer and methylation of the pyrrole 2-carboxyl moiety, and halogenation. For the first time, brominated products were detected. Their levels and the levels of non-halogenated products increased in medium supplemented with KBr. Based on the presented data, we propose that the enzyme promiscuity contributes to a broad product spectrum.
PubMed: 38864648
DOI: 10.1128/spectrum.00423-24 -
ELife Jun 2024DNA gyrase, a ubiquitous bacterial enzyme, is a type IIA topoisomerase formed by heterotetramerisation of 2 GyrA subunits and 2 GyrB subunits, to form the active...
DNA gyrase, a ubiquitous bacterial enzyme, is a type IIA topoisomerase formed by heterotetramerisation of 2 GyrA subunits and 2 GyrB subunits, to form the active complex. DNA gyrase can loop DNA around the C-terminal domains (CTDs) of GyrA and pass one DNA duplex through a transient double-strand break (DSB) established in another duplex. This results in the conversion from a positive (+1) to a negative (-1) supercoil, thereby introducing negative supercoiling into the bacterial genome by steps of 2, an activity essential for DNA replication and transcription. The strong protein interface in the GyrA dimer must be broken to allow passage of the transported DNA segment and it is generally assumed that the interface is usually stable and only opens when DNA is transported, to prevent the introduction of deleterious DSBs in the genome. In this paper, we show that DNA gyrase can exchange its DNA-cleaving interfaces between two active heterotetramers. This so-called interface 'swapping' (IS) can occur within a few minutes in solution. We also show that bending of DNA by gyrase is essential for cleavage but not for DNA binding per se and favors IS. Interface swapping is also favored by DNA wrapping and an excess of GyrB. We suggest that proximity, promoted by GyrB oligomerization and binding and wrapping along a length of DNA, between two heterotetramers favors rapid interface swapping. This swapping does not require ATP, occurs in the presence of fluoroquinolones, and raises the possibility of non-homologous recombination solely through gyrase activity. The ability of gyrase to undergo interface swapping explains how gyrase heterodimers, containing a single active-site tyrosine, can carry out double-strand passage reactions and therefore suggests an alternative explanation to the recently proposed 'swivelling' mechanism for DNA gyrase (Gubaev et al., 2016).
Topics: DNA Gyrase; Protein Multimerization; DNA, Bacterial; Escherichia coli; DNA
PubMed: 38856655
DOI: 10.7554/eLife.86722 -
Iranian Journal of Microbiology Apr 2024Shallots, recognized for their minimal toxicity, cost-effectiveness, and widespread availability, are increasingly considered a viable source of biological activity....
BACKGROUND AND OBJECTIVES
Shallots, recognized for their minimal toxicity, cost-effectiveness, and widespread availability, are increasingly considered a viable source of biological activity. This study evaluates the antibacterial efficacy of a specific shallot cultivar from Palu Valley, Indonesia, against , the pathogen responsible for typhoid fever.
MATERIALS AND METHODS
Utilizing thin-layer chromatography (TLC-bioautography) and gas chromatography-mass spectroscopy (GC-MS), the study identifies active compounds in shallot ethanol extract and employs molecular docking to assess interactions between receptors and ligands.
RESULTS
Findings indicate significant antibacterial activity, with a notable inhibition zone diameter of 31.5 mm at spot Rf 0.28 in TLC bioautography and an optimum concentration of 2% yielding an average clear zone diameter of 28.27 mm in the agar diffusion test. GC-MS analysis reveals 41 compounds, predominantly dodecanoic acid and 1,2,3-propanetriyl ester. Additionally, molecular docking reveals the lowest binding affinity (-7.3 kcal/mol) for Ergost-8-En-3-Ol, 14-Methyl-, (3.Beta,5. Alpha.) against DNA gyrase.
CONCLUSION
This study confirms Palu Valley shallot extract's potent antibacterial effect against highlighting its therapeutic potential.
PubMed: 38854984
DOI: 10.18502/ijm.v16i2.15354 -
Microbes and Environments 2024All cells must maintain the structural and functional integrity of the genome under a wide range of environments. High temperatures pose a formidable challenge to cells... (Review)
Review
All cells must maintain the structural and functional integrity of the genome under a wide range of environments. High temperatures pose a formidable challenge to cells by denaturing the DNA double helix, causing chemical damage to DNA, and increasing the random thermal motion of chromosomes. Thermophiles, predominantly classified as bacteria or archaea, exhibit an exceptional capacity to mitigate these detrimental effects and prosper under extreme thermal conditions, with some species tolerating temperatures higher than 100°C. Their genomes are mainly characterized by the presence of reverse gyrase, a unique topoisomerase that introduces positive supercoils into DNA. This enzyme has been suggested to maintain the genome integrity of thermophiles by limiting DNA melting and mediating DNA repair. Previous studies provided significant insights into the mechanisms by which NAPs, histones, SMC superfamily proteins, and polyamines affect the 3D genomes of thermophiles across different scales. Here, I discuss current knowledge of the genome organization in thermophiles and pertinent research questions for future investigations.
Topics: Archaea; Bacteria; Genome, Bacterial; Genome, Archaeal; Hot Temperature; DNA Topoisomerases, Type I; DNA Repair
PubMed: 38839371
DOI: 10.1264/jsme2.ME23087 -
RSC Advances May 2024The antibacterial efficacy of some newly developed C-3 carboxylic group-containing ciprofloxacin-linked 1,2,3-triazole conjugates was studied. Twenty-one compounds from...
Synthesis of ciprofloxacin-linked 1,2,3-triazole conjugates as potent antibacterial agents using click chemistry: exploring their function as DNA gyrase inhibitors - and -based studies.
The antibacterial efficacy of some newly developed C-3 carboxylic group-containing ciprofloxacin-linked 1,2,3-triazole conjugates was studied. Twenty-one compounds from three different series of triazoles were synthesized using click chemistry and evaluated for their antibacterial activity against nine different pathogenic strains, including three Gram-positive strains, (ATCC29212), (ATCC25923), (clinical isolate), and six Gram-negative bacterial strains, (ATCC25922), (ATCC27853), (clinical isolate), (clinical isolate), (clinical isolate) and (clinical isolate). Among the compounds, 10, 10a, 10b, 10c, 10d, 11a, 11f, 12c, 12e and 12f showed excellent activity with MIC values upto 12.5 μg mL, whereas the control ciprofloxacin showed MIC values of 0.781-25 μg mL towards various strains. In addition, the low toxicity profile of the synthesized molecules revealed that they are potent antibiotics. Molecular docking and MD analysis were performed using the protein structure of DNA gyrase B, which was further corroborated with an assay to evaluate the inhibition of DNA gyrase. The analysis revealed that compound 10b was the most potent inhibitor of DNA gyrase compared to ciprofloxacin, which was employed as the positive control. Furthermore, the structure of two title compounds (11a and 12d) was characterized using single-crystal analysis.
PubMed: 38818013
DOI: 10.1039/d4ra01332h -
RSC Advances May 2024This article contributes to the search for new therapeutic agents for treatment of diseases caused by bacterial pathogens. In this study, a new series of compounds...
This article contributes to the search for new therapeutic agents for treatment of diseases caused by bacterial pathogens. In this study, a new series of compounds incorporating numerous bioactive moieties such as quinazolin-2,4-dione, acylthiourea linkage, and/or five membered nitrogen heterocycles (pyrazole and oxazole) 2-5a-c was described to identify new antibacterial drug candidates inhibition of DNA gyrase enzyme. The precursor -['-(2-cyano-acetyl)-hydrazinocarbothioyl]-4-(2,4-dioxo-1,4-dihydro-2-quinazolin-3-yl)-benzamide 2 was prepared by treatment of compound 1 with ammonium thiocyanate and cyanoacetic acid hydrazide through multicomponent reaction (MCR). In addition, compounds 3a-d and 4a-b were synthesized by treatment of 2 with aromatic aldehydes and/or ketones through Knoevenagel reaction, affording high purity products in satisfactory yields. Moreover, new heterocyclic moieties such as pyrazole and/or oxazole attached to quinazolin-2,4-dione core 5a-c were synthesized by treatment of 3c with different nucleophilic reagents like hydrazine, phenyl hydrazine and hydroxyl amine, respectively. Subsequently, the obtained products were structurally characterized by IR, H-, C-NMR, and MS analyses. The minimum inhibitory concentration (MIC) and antibacterial potency of all compounds were estimated against two G-ve ( and ), and two G+ve bacteria ( and ). Encouragingly, compound 3c demonstrated the best antibacterial activity against all the strains of the tested pathogenic bacteria at low concentrations compared with the standard drug, Ciprofloxacin. Electron withdrawing groups such as -NO and -Cl enhance the antibacterial activity. Next, a molecular docking study between the synthesized derivatives and the target enzyme, DNA gyrase enzyme (PDB: 2xct) was undertaken to investigate intermolecular interactions between the compounds and target enzyme.
PubMed: 38808238
DOI: 10.1039/d4ra02960g