Person: SARIYAR AKBULUT, BERNA
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SARIYAR AKBULUT
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Publication Metadata only Potentiating the activity of berberine for Staphylococcus aureus in a combinatorial treatment with thymol(ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2020) SARIYAR AKBULUT, BERNA; Aksoy, Cemile Selin; Avci, Fatma Gizem; Ugurel, Osman Mutluhan; Atas, Basak; Sayar, Nihat Alpagu; Akbulut, Berna SariyarA plethora of natural products emerges as attractive molecules in the struggle against antibiotic resistance. These molecules impose their bioactivities not only alone but also in combinations as well, which further enhances their effects. Berberine is a well-known isoquinoline alkaloid with antibacterial activity. Unfortunately, it is readily extruded, which significantly reduces its efficacy and restricts its potential. Thymol is a monoterpenic phenol that exhibits different biological activities but its major effect is observed only at relatively high concentrations, which raises concern on cytotoxicity. The aim of the study was to potentiate the antibacterial activity of berberine, in a combination treatment with thymol in the opportunistic pathogen Staphylococcus aureus and understand the antibacterial mechanism of the combination treatment. The synergism of berberine and thymol was first established by the checkerboard assay. Then the antibacterial mechanism of the synergistic combination was explored by growth curves, biofilm formation assay, SEM observation, and RNA-Seq based transcriptomic profiling. Checkerboard assay showed that 32 mu g mL(-1) berberine and 64 mu g mL(-1) thymol was a synergistic combination, both concentrations below their cytotoxicity limits for many cells. 32 mu g mL(-1) berberine and 32 mu g mL(-1) thymol was sufficient to inhibit biofilm formation. SEM images confirmed the morphological changes on the structure of combination treated cells. The major finding of the combination treatment from the transcriptomic analysis was the repression in the expression of virulence factors or genes related to virulence factors. Apart from the particular changes related to the cell envelope, the majority of expressional changes seemed to be similar to berberine-treated cells or to be resulting from general stress conditions. The findings of this work showed that when thymol was used in combination with berberine, it enhanced the antibacterial activity of berberine in a synergistic manner. Furthermore, thymol could be considered as an antivirulence agent, disarming S. aureus cells.Publication Open Access Piperidine-based natural products targeting type IV pili antivirulence: a computational approach(2023-03-01) SARIYAR AKBULUT, BERNA; ÖZBEK SARICA, PEMRA; Ozcan A., Keskin O., Sariyar Akbulut B., Özbek Sarica P.© 2022 Elsevier Inc.Type IV (T4) pilus is among the virulence factors with a key role in serious bacterial diseases. Specifically, in Neisseria meningitidis and Pseudomonas aeruginosa, it determines pathogenicity and causes infection. Here, a computational approach has been pursued to find piperidine-based inhibitor molecules against the elongation ATPase of T4 pili in these two selected pathogens. Using the modeled structures of the PilF and PilB ATPases of N. meningitidis and P. aeruginosa, virtual library screening via molecular docking has returned inhibitor molecule candidates. The dynamics of the best three binders have further been investigated in detail via molecular dynamic simulations. Among these, ligands with COCONUT IDs CNP0030078 and CNP0051517 were found to have higher potential in the inhibition of ATPases based on molecular dynamic simulation analysis and biological activity information. The obtained results will guide future efforts in antivirulence drug development against T4 pili of N. meningitidis and P. aeruginosa.Publication Open Access Identification of novel inhibitors of the ABC transporter BmrA(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020-12) SARIYAR AKBULUT, BERNA; Sercinoglu, Onur; Senturk, Duygu; Kaya, Fatma Ece Altinisik; Avci, Fatma Gizem; Frlan, Rok; Tomasic, Tihomir; Ozbek, Pemra; Orelle, Cedric; Jault, Jean-Michel; Akbulut, Berna SariyarThe resistance of microbes to commonly used antibiotics has become a worldwide health problem. A major underlying mechanism of microbial antibiotic resistance is the export of drugs from bacterial cells. Drug efflux is mediated through the action of multidrug resistance efflux pumps located in the bacterial cell membranes. The critical role of bacterial efflux pumps in antibiotic resistance has directed research efforts to the identification of novel efflux pump inhibitors that can be used alongside antibiotics in clinical settings. Here, we aimed to find potential inhibitors of the archetypical ATP-binding cassette (ABC) efflux pump BmrA of Bacillus subtilis via virtual screening of the Mu.Ta.Lig. Chemotheca small molecule library. Molecular docking calculations targeting the nucleotide-binding domain of BmrA were performed using AutoDock Vina. Following a further drug-likeness filtering step based on Lipinski's Rule of Five, top 25 scorers were identified. These ligands were then clustered into separate groups based on their contact patterns with the BmrA nucleotide-binding domain. Six ligands with distinct contact patterns were used for further in vitro inhibition assays based on intracellular ethidium bromide accumulation. Using this methodology, we identified two novel inhibitors of BmrA from the Chemotheca small molecule library.Publication Open Access A two-step purification platform for efficient removal of Fab-related impurities: A case study for Ranibizumab(2023-11-01) PİNAR, ORKUN; SARIYAR AKBULUT, BERNA; KAZAN, DİLEK; Tatli O., Oz Y., Dingiloglu B., Yalcinkaya D., Basturk E., Korkmaz M., Akbulut L., Hatipoglu D., Kirmacoglu C., Akgun B., et al.Antibodies (mAbs) and antibody fragments (Fabs) constitute one of the largest and most rapidly expanding groups of protein pharmaceuticals. In particular, antibody fragments have certain advantages over mAbs in some therapeutic settings. However, due to their greater chemical diversity, they are more challenging to purify for large-scale production using a standard purification platform. Besides, the removal of Fab-related byproducts poses a difficult purification challenge. Alternative Fab purification platforms could expedite their commercialization and reduce the cost and time invested. Accordingly, we employed a strong cation exchanger using a pH-based, highly linear gradient elution mode following Protein L affinity purification and developed a robust two-step purification platform for an antibody fragment. The optimized pH gradient elution conditions were determined on the basis of purity level, yield, and the abundance of Fab-related impurities, particularly free light chain. The purified Fab molecule Ranibizumab possessed a high degree of similarity to its originator Lucentis. The developed purification platform highly intensified the process and provided successful clearance of formulated Fab- and process-related impurities (∼98 %) with an overall process recovery of 50 % and, thus, might be a new option for Fab purification for both academic and industrial purposes.Publication Open Access Curcumin displays enhanced solubility and antibacterial activities when complexed with the cell penetrating peptide pVEC(2022-06-01) SARIYAR AKBULUT, BERNA; Koleoglu E., Acar T., DERMAN S., SARIYAR AKBULUT B.Curcumin is among phytochemicals with increasing popularity; unfortunately, its therapeutic potential is restricted due to poor water solubility and bioavailability. The current work undertakes the effort to improve the therapeutic potential of curcumin by complexing it with a cell penetrating peptide using copper ions. A mononuclear complex was synthesized from copper(II) acetate and curcumin. Then this complex was conjugated to the cell penetrating peptide, pVEC. The structural characterization of the complexes was achieved using UV-Vis and Fourier transform infrared spectroscopies. Dynamic and electrophoretic light scattering measurements have confirmed the complexation of curcumin with the peptide to form nanoparticles. Both solubility and kinetic stability of curcumin greatly improved upon complex formation with pVEC through copper ions. Then the antibacterial activity of curcumin in the complex was tested. The amount of curcumin in the minimum inhibitory concentration was similar to 30, similar to 8, and similar to 15 fold lower, respectively for Escherichia coli, Bacillus subtilis, and Staphylococcus aureus when complexed with pVEC; however, this improvement was specifically noteworthy for the gram-negative E. coli since the contribution of pVEC in the complex to the observed activity was negligible in this bacterium. With enhanced solubility and stability, metallo curcumin conjugated pVEC complex possesses potential for different therapeutic applications.Publication Open Access Tyrosinase-based production of L-DOPA by Corynebacterium glutamicum(SPRINGER, 2021-12) SARIYAR AKBULUT, BERNA; Kurpejovic, Eldin; Wendisch, Volker F.; Akbulut, Berna SariyarAn increase in the number of elderly people suffering from the symptoms of Parkinson's disease is leading to an expansion in the market size of 3,4-dihydroxyphenyl-l-alanine (l-DOPA), which is the most commonly used drug for the treatment of this disease. Need for better quality products through economically feasible and sustainable processes makes biotechnological approaches attractive. The current study is focused on heterologous expression of Ralstonia solanacearum tyrosinase in Corynebacterium glutamicum cells to produce l-DOPA during growth on glucose or glucose/xylose mixtures. Whole-cells pre-grown on glucose were further exploited for biotransformation of l-tyrosine to l-DOPA. To prevent l-DOPA oxidation, not only the most commonly used agent, ascorbic acid, but also for the first time, thymol was evaluated. The highest l-DOPA titer was 0.26 +/- 0.02 g/L at the end of growth on a mixture of 1% xylose and 3% glucose in the presence of 200 mu M thymol as the oxidation inhibitor. The ability to co-utilize glucose and xylose to reach this titer could make these cells ideal for l-DOPA production using hydrolyzed lignocellulosic biomass. When the pre-grown cells were further used for biotransformation, the highest l-DOPA yield was 0.61 +/- 0.02 g/gDCW with 4 mM ascorbic acid. Since l-tyrosine biotransformation is primarily dependent on tyrosinase activity, yield in this route could be improved by optimizing reaction conditions. As the industrial workhorse for amino acid production, these C. glutamicum cells will clearly benefit from strain development efforts and bioprocess optimization towards sustainable and economically feasible l-DOPA production.Publication Metadata only Screening of FDA-Approved Natural Drugs as Anti-Virulence Agents Against Pseudomonas aeruginosa and Neisseria meningitides.(2022-06-30) KULA, CEYDA; ÖZBEK SARICA, PEMRA; SARIYAR AKBULUT, BERNA; Özcan A., Kula C., Avcı F. G., Keskin Özkaya Z. Ö., Özbek Sarıca P., Sarıyar Akbulut B.Publication Open Access Carvacrol enhances the antimicrobial potency of berberine in bacillus subtilis(2022-05-01) SAYAR, NİHAT ALPAGU; SARIYAR AKBULUT, BERNA; Atas B., Aksoy C. S., Avci F. G., SAYAR N. A., Ulgen K., ÖZKIRIMLI ÖLMEZ E., SARIYAR AKBULUT B.The essential oil carvacrol from oregano displays a wide range of biological activities among which is found the inhibition of efflux pumps. Thus, using carvacrol, the current work undertook the effort to potentiate the antimicrobial activity of berberine, a natural product with limited antimicrobial efficacy due to its efflux. Following the selection of concentrations for the combinatorial treatments, guided by checkerboard microtiter plate assay and growth experiments, ethidium bromide accumulation assay was used to find that 25 mu g mL(-1) carvacrol displayed a weak efflux pump inhibitor character in Bacillus subtilis. Scanning electron microscopy images and cellular material leakage assays showed that carvacrol at this concentration neither altered the morphology nor the permeability of the membrane alone but when combined with 75 mu g mL(-1) berberine. Among the efflux pumps of different families found in B. subtilis, except for BmrA and Mdr, the increase in the expressional changes was striking, with Blt displaying similar to 4500-fold increase in expression under the combination treatment. Overall, the findings demonstrated that carvacrol potentiated the effect of berberine; however, not only multiple pumps but also different targets may be responsible for the observed activity.Publication Open Access Curvularia lunata: A fungus for possible berberine transformation(2022-01-01) SARIYAR AKBULUT, BERNA; Yılmaz D., AVCI F. G., SARIYAR AKBULUT B.Abstract: The prevalence of multidrug-resistant microorganisms results in an urgent need for the development of new antimicrobial agents or new treatment strategies. In this sense, plants serve different alternatives. Berberine, a plantderived compound, is one of the alkaloids known to display antimicrobial activity against several types of microorganisms, while its being a substrate of various efflux pumps causes a decrease in its efficacy. Biotransformation makes it possible to obtain novel or more effective compounds with only minor structural modifications using enzyme systems. In this study, biotransformation of berberine by Curvularia lunata was examined. The working concentration of berberine was determined by observing the microbial growth on agar plates. The concentration of residual berberine in the media was analyzed by HPLC. In addition, laccase and beta-glucosidase enzyme activities were followed for their possible roles during the biotransformation of berberine. The results show that at the end of 14 days, C. lunata consumed 99% and 87% of berberine with the initial concentrations of 0.35 mg/mL and 0.5 mg/mL, respectively. Enzyme activities were not affected significantly. Since the concentration of berberine decreased, the biotransformation of berberine by C. lunata could be mentioned. Monitoring of biotransformation products plays a crucial role in discovering novel antimicrobial compounds and new valuable molecules.Publication Metadata only Live Cell Imaging of Peptide Uptake Using a Microfluidic Platform(SPRINGER, 2021) SARIYAR AKBULUT, BERNA; Yuce, Merve; Ozkirimli, Elif; Sariyar Akbulut, Berna; Ulgen, KutluCell penetrating peptides (CPPs) are unique molecules with the ability to pass through biological membranes as they carry their cargoes into the cells. Endocytosis and direct penetration have been proposed as the two major mechanisms for their internalization. However, the involvement of oligo peptide permease (Opp) in bacterial CPP uptake is an issue that yet remains to be elucidated. Here, a microfluidic platform coupled with live cell imaging was used to monitor CPP uptake in Escherichia coli. The set-up enabled imaging on a single-cell basis, helped to capture cell dynamics at a micro-scale and provided quantitative real-time information. The constructed platform also provided evidence on the contribution of Opp to peptide uptake. Additional high-resolution visualization under confocal microscopy confirmed that in the absence of Opp, the internalized peptides accumulated in the periplasm. Here, we have shown that microfluidic platforms, which have successful applications in different areas, can be used as a highly reliable and versatile tool for studying peptide uptake in bacterial cells.