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Öğe Antimicrobial and antiproliferative activity studies of some new quinoline-3-carbaldehyde hydrazone derivatives(Academic Press Inc Elsevier Science, 2020) Puskullu, Mustafa Orhan; Celik, Ismail; Erol, Meryem; Fatullayev, Hanifa; Uzunhisarcikli, Ebru; Kuyucuklu, GulcanIn this study, a total of 22 piece quinoline-3-carbaldehyde hydrazone derivative compounds were designed and synthesized, 2 of which were not original, their antimicrobial activities were determined with microdilution method and their in vitro cytotoxic effect was investigated in MCF-7 and A549 cells by MTT assay. When the activity results are examined, although the antimicrobial effects of quinoline derivatives, in general, are weaker than standard drugs; 3q5 and 3q6 against MRSA showed promising activity with MIC:16 mu g/ml compared to reference drugs. Compounds generally showed weaker cytotoxic activity on the A549 and MCF-7 cell line. 3q12, 3q17 and 3q22 at 100 mu M reduced cell viability to 59.28%, 76.24% and 72.92% on A549 cells, respectively. Compound 3q6, one of the most effective compounds against MRSA, formed a 2.10 angstrom long hydrogen bond between the quinoline nitrogen and ARG132 in the DNA topoisomerase IV active site (PDB: 3FV5). Theoretical ADME profiles of all compounds comply with Lipinski and other limiting rules. In addition, MEP analysis of 3q6, geometric optimization and molecular reactivity analysis were calculated with the 6-311G (d,p) base set DFT/ B3LYP theory, and Delta E = ELUMO-EHOMO, which is a measure of the stable structure of the molecule, was cal-culated as 0.13377 for 3q6 and had the most stable electronic structure among all compounds.Öğe Effect of N-acetylcystein on Antibiofilm Efficiency of Antibiotics in Staphylococci Isolates(Ankara Microbiology Soc, 2021) Kuyucuklu, Gulcan; Onurdag, Fatma Kaynak; Eryildiz, CananBiofilms are often responsible for the difficulties in the treatment of infectious diseases due to their properties that facilitate escape from antibiotic effect and their antiphagocytic effects. At least 65% of all infectious diseases are associated with biofilm-forming bacteria. As Staphylococcus aureus and Staphylococcus epidermidis are among the most common agents of hospital infections and the infections are mostly biofilm-related, they pose an important problem. In infectious isolates, the minimum biofilm eradication concentration (MBEK) values of biofilm forms are much higher than the minimum inhibition concentration (MIC) values of planktonic forms. This situation requires the use of much higher doses of antibiotics in the treatment of infections and causes an increase in antibiotic resistance. The N-acetylcysteine (NAC) molecule is known to be effective against biofilm by disrupting mature biofilms and reducing the adhesion of bacteria to surfaces. In this study, it was aimed to demonstrate i) the biofilm-forming abilities ii) the change in ampicillin and vancomycin MIC values in the presence of NAC molecules, iii) the change in the MBEK values of these antibiotics in the presence of NAC molecule and iv) the change in the expression levels of genes thought to be related to biofilm formation in the presence of the NAC molecule among S.aureus (n= 38) and S.epidermidis (n= 12) isolates isolated from various clinical specimens in Trakya University Health Research and Application Center. In this study, microplate crystal violet method was used to demonstrate the biofilm formation in staphylococci. Broth microdilution and checkerboard method were used to demonstrate the change in the presence of NAC molecule of the MIC and MBEC values of ampicillin and vancomycin. The effect of NAC on the expression of intercellular binding proteins A and D (icaA, icaD) and Staphylococcus regulatory protein A (sarA) genes, which are the genes involved in biofilm formation in staphylococci, was determined by quantitative real-time Polymerase Chain Reaction (qRt-PCR) method. The Student-t test was used to compare the control and experimental groups (concentrations detected with synergy and additive effect); p< 0.05 was accepted as the limit value of significance. In this study, when the NAC molecule was used together with ampicillin and vancomycin, it was determined that this combination lowers the MIC values of staphylococcus isolates and staphylococcal biofilm MBEK values; and also the expression levels of icaA, icaD and sarA which were effective in biofilm formation in staphylococci have not changed and decreased. As a result, in this study, it has been determined that the NAC molecule can be a new alternative for combined drug therapy and is promising in terms of bringing a new approach to treatment. In addition, it is thought that it is possible to use the NAC molecule together with different microorganisms and antimicrobial agents, and the results obtained in this study are considered to be guiding for further studies on this subject.Öğe In VitroandIn SilicoStudies of Quinoline-2-Carbaldehyde Hydrazone Derivatives as Potent Antimicrobial Agents(Taylor & Francis Ltd, 2022) Celik, Ismail; Erol, Meryem; Puskullu, Mustafa Orhan; Uzunhisarcikli, Ebru; Ince, Ufuk; Kuyucuklu, Gulcan; Suzen, SibelWe previously synthesized a series of quinoline-2-carbaldehyde hydrazone derivatives and evaluated their antioxidant activities. In this study, the antimicrobial activities of these quinoline-2-carbaldehyde hydrazone derivatives were evaluated antimicrobial activity by the microdilution method, and there cytotoxic effect was investigated in MCF-7 and A549 cells by MTT assay. When the activity results were examined, although the antimicrobial activity of quinoline derivatives were equal or better than standard drugs in general, compound4(2 mu g/mL) and8(1 mu g/mL) againstE. faecalisand5(8 mu g/mL) againstP. aeruginosaare the most effective derivatives of the series. Besides, disk diffusion test was applied to these three compounds, and significant zone formation was observed at8(7 mm) compared to vancomycin (9 mm). Compounds showed no antiproliferative in A549 and MCF-7 cell lines, and compound4, 5,and8, which showed the most effective antimicrobial activity, were examined in healthy cells (Beas-2b) and no effect on cell viability was found. To understand the mechanism of this action of these compounds againstE. faecalis, molecular docking studies were performed on 15 different proteins, and it was concluded that the compounds interacted with FabH and not enough with other protein structures. The theoretical ADME profiles of compounds comply with Lipinski and other limiting rules. Also, some theoretical quantum parameters (HOMO-LUMO) of compounds, and both MEP analysis and geometric optimization analysis of8were calculated with 6-311 G (d,p) base set and DFT/B3LYP theory, and the results were shown.Öğe Investigation of antimicrobial resistance and virulence genes of Campylobacter isolates from patients in a tertiary hospital in Edirne, Turkey(Elsevier, 2020) Eryildiz, Canan; Tabakcioglu, Kiymet; Kuyucuklu, Gulcan; Sakru, NerminPurpose: Campylobacter is one of the most common pathogens that cause food-borne infections worldwide. The aim of this study was to determine the antimicrobial resistance rates and the presence of multiple virulence genes in Campylobacter isolates obtained from humans. Materials and Methods: In this study, 71 Campylobacter isolates obtained from human faecal samples were used. Antimicrobial susceptibility tests were performed through the gradient strip method. The presence of virulence genes was investigated by monoplex and multiplex polymerase chain reaction. Results: The rate of resistance of the 66 Campylobacter jejuni isolates was 12.1% for erythromycin, 40.9% for tetracycline and 68.2% for ciprofloxacin. Only one of five Campylobacter coli isolates was resistant to these three antimicrobial agents. The flaB, pldA, cdtA, cadF, cdtC and ceuE genes were found in all 66 of the C. jejuni isolates. In the C. jejuni isolates, positivity rates of 92.4% for flaA, 96.7% for cdtB, 98.5% for ciaB, 90.9% for dnaJ and 96.7% for racR were observed. The flaA, flaB, ciaB, cdtA and cdtC genes were present in all C. coli isolates. Conclusions: It was detected that there is an increase in antimicrobial resistance of Campylobacter strains in our region, and most of the isolates harbour virulence genes.Öğe Investigation of Antimicrobial Susceptibilities and Resistance Genes of Campylobacter Isolates from Patients in Edirne, Turkey(Iranian Scientific Society Medical Entomology, 2022) Eryildiz, Canan; Sakru, Nermin; Kuyucuklu, GulcanBackground: We aimed to determine the susceptibility of Campylobacter isolates obtained from patients to various antimicrobial agents and to investigate some related antimicrobial resistance genes. Methods: Fifty-six Campylobacter isolates obtained from fecal specimens by conventional methods at the Trakya University Health Center for Medical Research and Practice, Department of Medical Microbiology in Edirne, Turkey, from 2017-2017 were included. Antimicrobial susceptibilities were investigated by the gradient strip test method, and species determination was made by multiplex polymerase chain reaction (mPCR). The presence of the erm(B) gene and tet(O) gene was investigated in all isolates by PCR. DNA sequence analysis was performed to detect the presence of mutations in the 23S rRNA positions 2074 and 2075 in five isolates, including two erythromycin resistant isolates. The gyrA gene mutation was investigated by the mismatch amplification mutation assay (MAMA)-PCR. Results: In 54 C. jejuni isolates, resistance to erythromycin was 3.7%; to tetracycline, 59.3%; and to ciprofloxacin, 74.1%. Phenotypically, the tet(O) gene was detected in 33 tetracycline-resistant isolates, but no erm(B) gene was found in any of the Campylobacter isolates. As a result of the DNA sequencing, it was found no mutations in the 23S rRNA gene at the 2074 and 2075 positions. The gyrA mutation was observed in all 41 ciprofloxacin resistant Campylobacter isolates. Conclusion: Among the antimicrobial agents tested, ciprofloxacin had the highest resistance rate, and erythromycin had the lowest. Antimicrobial resistance in Campylobacter increased significantly compared with previously studies in our region as well as in the entire world. Monitoring the resistance to antimicrobial agents used to treat Campylobacter infections is important in determining empiric antimicrobial treatment.Öğe Investigation of TNF-?, LT-? and TNFR-2 gene Polymorphisms in Patients with Periodontitis in Turkey(Amber Publication, 2020) Ozkan-Kotiloglu, Selin; Kuyucuklu, Gulcan; Baltacioglu, Esra; Guncu, Guliz; Dursun, Erhan; Sukuroglu, Erkan; Karabulut, ErdemIntroduction: One of the cytokines involved in periodontal breakdown in periodontitis is; Tumor necrosis factor (TNF), with two types; tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin-alpha (LT-alpha). Aim: In the present study, the individual frequency of TNF-alpha -308 promoter, LT-alpha +252 intron, and TNF receptor-2 (TNFR-2) +587 exon polymorphisms associated with chronic (CP) and generalized aggressive periodontitis (GAP) were evaluated in Turkish population. Materials and Methods: This research was conducted on 224 periodontitis patients (P) (119 CP, 105 GAP patients) and 85 healthy controls (C). Blood samples were collected, and specific DNA regions were amplified by PCR method. Investigated gene polymorphisms were determined by RFLP (Restriction Fragment Length Polymorphism). Statistical analyses, including linkage analyses were performed. Results: While there was no statistically significant difference in LT-alpha +252 polymorphisms between the patients and controls, significant associations between TNF-alpha-308 GA genotype and CP and GAP were determined. For TNFR-2 (+587) T/G polymorphism; TT, TG and GG genotype and allele frequencies were analysed and significant differences were found in genotype and allele frequencies between the control and CP and GAP groups (p<0,001). Conclusion: This is the first study investigating the TNF-alpha, LT-alpha and TNFR-2 polymorphisms in CP and GAP in Turkish population. Significant differences were found in genotype and allele frequencies, in CP and GAP groups.Öğe Molecular modeling, density functional theory, ADME prediction and antimicrobial activity studies of 2-(substituted)oxazolo[4,5-b]pyridine derivatives(Royal Soc Chemistry, 2021) Celik, Ismail; Erol, Meryem; Kuyucuklu, GulcanIn this study, the antimicrobial activities of previously synthesized 2-(substituted)oxazolo[4,5-b]pyridine derivatives toward six bacteria strains and twelve related drug-resistant isolates, and one fungus strain and two related drug-resistant isolates were investigated via the microdilution method. P6 (2-(4-trifluoromethylphenyl)oxazolo[4,5-b]pyridine) and P7 (2-(4-trifluoromethoxyphenyl)oxazolo[4,5-b]pyridine) showed better activity against E. faecalis isolate and E. coli isolate than ampicillin with a MIC of 16 mu g mL(-1). In addition, P5 (2-(4-methoxyphenyl)oxazolo[4,5-b]pyridine) and P6 showed gentamicin-equivalent activity against P. aeruginosa, with a MIC of 16 mu g mL(-1), while P7 showed better activity than gentamicin, with a MIC of 8 mu g mL(-1). The compounds generally showed good to strong antimicrobial activities. Molecular docking and molecular dynamics simulations of the compounds were performed using the DNA gyrase enzyme, and the interactions were evaluated. The compounds showed an overlap at the DNA gyrase ATP binding site with similar protein-ligand interactions. Average RMSD values of the apo form, and P5-4KTN, P6-4KTN and P7-4KTN holo forms were measured to be 0.149 nm, 0.152 nm, 0.165 nm, and 0.146 nm, respectively. The P7 ligand stabilized the protein via further increasing its stability. HOMO-LUMO orbital energies and other electronic parameters derived from these energies, MEP and NBO analysis, and geometric optimization were obtained using DFT/B3LYP theory and the 6-311G(d,p) basis set. The LUMO-HOMO Delta E values for the most active compounds, P5, P6 and P7, are 4.3508, 4.4471, and 4.4852 eV, respectively. The predicted ADME profiles of the compounds were calculated, and they were compliant with Lipinski and other restrictive rules.Öğe Serological Follow-up of Human Cystic Echinococcosis in the Thrace Region, Turkey(Iranian Scientific Society Medical Entomology, 2022) Eryildiz, Canan; Tarladacalisir, Taner; Kuyucuklu, Gulcan; cakmakci, Berrak; Sakru, NerminBackground: Parasites of the genus Echinococcus are common worldwide and are important cestodes that cause serious infections in humans and animals. This retrospective study evaluated the indirect hemagglutination (IHA) test results of serum samples obtained from patients with a pre-diagnosis of cystic echinococcosis (CE) within ten years. In addition, the role of the IHA test results of the patients in the follow-up of the treatment and determining possible recurrences was investigated.Methods: The IHA test results of 2426 serum samples of patients with a pre-diagnosed CE admitted to Trakya University Health Center for Medical Research and Practice in Edirne, Turkey, between January 2011 and December 2020 were evaluated retrospectively. The data of 53 patients with CE who had medical treatment and/or postoperative follow-up serological records were evaluated.Results: Of 2426 IHA tests, 376 (15.5%) were seropositive, and 2050 (84.5%) were seronegative. It was determined that 376 serum samples detected as positive belonged to 207 patients with CE. Of 207 CE patients, 109 (52.7%) were female and 98 (47.3%) were male. The most common organ involvement was the liver in 186 (89.9%) cases. Of 53 patients, 16 were considered relapse cases. The median follow-up period for 16 recurrent cases was 31.8 (1-77) months. Our results showed a statistically significant correlation between long-term serological follow-up and recurrence detection (P=0.034).Conclusion: Long-term serological follow-up after treatment is considered useful in determining possible recurrent cases. CE is an important public health problem for endemic regions, including our country, and we think our study results will contribute to the status and follow-up of the disease.Öğe Synthesis, Antimicrobial Activity, and Molecular Modeling Studies of Some Benzoxazole Derivatives(Bentham Science Publ Ltd, 2022) Muhammed, Muhammed Tilahun; Kuyucuklu, Gulcan; Kaynak-Onurdag, Fatma; Aki-Yalcin, EsinBackground: The need to develop novel antimicrobial agents is apparent as infectious diseases are increasing and resistance is rapidly developing against the drugs used in the treatment. Objective: This study aimed at the synthesis, antimicrobial susceptibility testing, and computational elucidation of the mechanism of action of benzoxazole derivatives. It also aimed to compare the results obtained in this study with the previous studies by our group. This would pave the way for designing novel molecules with better antimicrobial activity. The other goal was pharmacophore analysis and in silico ADMET analysis of them. Methods: In this study, synthesis, antimicrobial susceptibility testing, molecular docking, pharmacophore analysis, and ADMET prediction were carried out. Results: The antimicrobial activity studies demonstrated that the synthesized compounds were active against standard strains and clinical isolates at high concentrations. Then, the antimicrobial testing results were compared to similar benzoxazoles tested by our group previously. Benzoxazole derivatives without a methylene bridge between oxazole and phenyl ring were found to be more active than those with the methylene bridge. This was also confirmed by molecular modeling undertaken in this study. The computational results indicated that the antibacterial activity could be achieved by DNA gyrase inhibition. Pharmacophore analysis showed that hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), and hydrophobicity features would contribute to the inhibition. In addition, in silico ADMET property investigation of the compounds exhibited that they had the desired pharmacokinetics. Conclusion: Although antibacterial activity by inhibiting DNA gyrase is selective, the synthesized compounds were active at much higher concentrations than the standards. Therefore, in prospective antimicrobial studies, it is better to focus on benzoxazole derivatives without the methylene bridge. Since the compounds had suitable in silico ADMET properties, screening them against the other pharmacologic activities should be carried out. It is recommended to support the molecular modeling results with in vitro or in vivo studies.Öğe Synthesis, Molecular Docking, and DFT Studies of Some New 2,5-Disubstituted Benzoxazoles as Potential Antimicrobial and Cytotoxic Agents(Taylor & Francis Ltd, 2022) Erol, Meryem; Celik, Ismail; Uzunhisarcikli, Ebru; Kuyucuklu, GulcanIn this study, a total of 17 piece 2,5-disubstituted benzoxazole derivatives were synthesized, 2 of which were not original, their antimicrobial activities were determined using microdilution method and theirin vitrocytotoxic activities were investigated on MCF-7 and A549 cells by MTT test. When the activity results are examined, although the antibacterial effects of benzoxazole derivatives are weaker than standard drugs;3N13and3N19againstCandida albicansisolate showed the closest activity to fluconazole with MIC: 16 mu g/ml. The cytotoxicity test was measured at a concentration of 100 mu M and a 24-h incubation period. The results showed that the compounds had weak activities against two cell lines. Molecular docking studies of synthesized compounds were performed on sterol 14 alpha-demethylase protein (CYP51) and protein-ligand interactions of3N13, the most effective derivative againstC. albicansisolate, were showed (PDB: 5TZ1). Estimated ADME profiles of compounds were calculated and also3N13's were calculated HUMO-LUMO energies, molecular electrostatic potential analysis, and geometric optimization parameters with 6-311 G+ (d,p) base set using DFT/B3LYP theory, and the results were displayed.Öğe Synthesis, Molecular Docking, Molecular Dynamics, DFT and Antimicrobial Activity Studies of 5-substituted-2-(p-methylphenyl)benzoxazole Derivatives(Elsevier, 2021) Erol, Meryem; Celik, Ismail; Kuyucuklu, GulcanIn this study, new 2-(p-methylphenyl)-5-(2-substitutedacetamido)benzoxazole derivatives were synthesized, and antimicrobial activities on six bacteria and their twelve drug-resistant isolates and one fungus and its two drug-resistant isolates were investigated by microdilution method. B1 against Staphylococcus aureus isolate, and B1 and B2 against Escherichia coli isolate showed more potent antimicrobial activity with MIC value of 16 mu g/mL than some of the reference drugs. The compounds' interactions on the DNA gyrase enzyme were evaluated by molecular docking and molecular dynamics simulations. Docked compounds have demonstrated superimposition in the DNA gyrase ATP binding site with similar protein-ligand interactions. With 50 ns duration molecular dynamics simulations, the average RMSD value of the DNA gyrase subunit B protein and B1, B2, B3, and B4 complexes were measured at about 0.15 nm. The ligands-bound DNA gyrase subunit B protein is a little less RMSF value and more stable than the apoprotein form between 45-49 residues in the active site amino acids region. Geometric optimization parameters, HOMO-LUMO orbital energies, and other electronic parameters derived from these energies, MEP, and NBO analysis were performed the DFT/B3LYP theory and 6-311G (d,p) basis set. The Delta E: LUMO-HOMO of the two most active compounds B1 and B2 are 4.2928 and 4.3219, respectively. The compounds' predicted ADME profiles were in line with Lipinski and other limiting rules. (C) 2021 Elsevier B.V. All rights reserved.
