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 Metadata only Proteomics Evidence for the Activity of the Putative Antibacterial Plant Alkaloid (-)-Roemerine: Mainstreaming Omics-Guided Drug Discovery(MARY ANN LIEBERT, INC, 2015) SARIYAR AKBULUT, BERNA; Gokgoz, Nilay Budeyri; Akbulut, Berna SariyarDiscovery of new antibacterials with novel mechanisms is important to counteract the ingenious resistance mechanisms of bacteria. In this connection, omics-guided drug discovery offers a rigorous method in the quest of new antibacterials. (-)-Roemerine is a plant alkaloid that has been reported to possess putative antibacterial activity against Escherichia coli, Bacillus subtilis, and Salmonella typhimurium. The aim of the present study was to characterize the activity of (-)-roemerine in Escherichia coli TB1 using proteomics tools. With (-)-roemerine treatment, we found limited permeability through the outer membrane and repression of transport proteins involved in carbohydrate metabolism, resulting in poor carbon source availability. The shortfall of intracellular carbon sources in turn led to impaired cell growth. The reduction in the abundance of proteins related to translational machinery, amino acid biosynthesis, and metabolism was accompanied by a nutrient-limited state. The latter finding could suggest a metabolic shutdown in E. coli cells. High osmolarity was clearly not one of the reasons of bacterial death by (-)-roemerine. These observations collectively attest to the promise of plant omics and profiling of putative drug candidates using proteomics tools. Omics-guided drug discovery deserves greater attention in mainstream pharmacology so as to better understand the plants' medicinal potentials.Publication Open Access Repurposing bioactive aporphine alkaloids as efflux pump inhibitors(ELSEVIER, 2019-11) SARIYAR AKBULUT, BERNA; Avci, Fatma Gizem; Atas, Basak; Aksoy, Cemile Selin; Kurpejovic, Eldin; Toplan, Gizem Gulsoy; Gurer, Caglayan; Guillerminet, Maxime; Orelle, Cedric; Jault, Jean-Michel; Akbulut, Berna SariyarExtrusion of drugs or drug-like compounds through bacterial efflux pumps is a serious health issue that leads to loss in drug efficacy. Combinatorial therapies of low-efficacy drugs with efflux pump inhibitors may help to restore the activities of such drugs. In this quest, natural products are attractive molecules, since in addition to their wide range of bioactivities they may inhibit efflux pumps. The current work repurposed the bioactive alkaloid roemerine as a potential efflux pump inhibitor. In Bacillus subtilis, both Bmr and BmrA, belonging to the major facilitator and the ATP-binding cassette superfamilies, respectively, were found to be inhibited by roemerine. Scanning electron microscopy and RNA-Seq analyses showed that it potentiated the effect of berberine. Growth rates and checkerboard assays confirmed the synergy of roemerine and berberine and that roemerine prevented berberine efflux by inhibiting Bmr. Transport assays with inverted membrane vesicles prepared from Escherichia cob overexpressing BmrA showed that increasing roemerine concentration decreased the transport of doxorubicin, the BmrA substrate, confirming that roemerine may also be considered as an inhibitor of BmrA. Thus, these findings suggest that conjugation of roemerine to substrates of efflux pumps, Bmr and BmrA, may help to potentiate the activity of their drug substrates.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 Interplay of adaptive capabilities of Halomonas sp AAD12 under salt stress(SOC BIOSCIENCE BIOENGINEERING JAPAN, 2012) SARIYAR AKBULUT, BERNA; Ceylan, Selim; Yilan, Gulsah; Akbulut, Berna Sariyar; Poli, Annarita; Kazan, DilekIn the present study, osmoadaptive mechanism of Halomonas sp. AAD12 was studied through analysis of changes in its proteome maps and osmolyte accumulation strategy to understand how this euryhaline microorganism masters osmotic stress of saline environments. Under salt stress, there were significant variations in the expression of proteins involved in osmoregulation, stress response, energy generation and transport. This was accompanied by an increase in proline and hydroxyectoine but a decrease in ectoine accumulation. The major osmolyte at high salinity was proline. Unexpectedly the size of the total ectoines' pool was smaller at elevated salinity. Experimental findings were then integrated with a metabolic model to get insight into carbon trafficking during osmoadaptation. Simulations predicted that the total flux through energy generating pathways, namely gluconeogenesis and the pentose phosphate pathway, was significantly lower and carbon source that entered the system as citrate was mainly diverted to osmolyte synthesis at high salinity. Overall these results suggested that the moderately halophilic Halomonas sp. AAD12 pursued a different osmoregulatory strategy than the two well known moderate halophiles, Chromohalobacter salexigens and Halobacillus halophilus. The climbing value of osmolytes such as ectoine in health care and skin care products places significant attention to halophilic microorganisms hence an understanding of the osmoadaptive mechanism and osmolyte accumulation strategy of this isolate is very valuable to be able to manipulate its metabolism towards desired goals. (C) 2012, The Society for Biotechnology, Japan. All rights reserved.Publication Metadata only Monte Carlo sampling and principal component analysis of flux distributions yield topological and modular information on metabolic networks(ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD, 2006) SARIYAR AKBULUT, BERNA; Sariyar, Berna; Perk, Sinem; Akman, Ugur; Hortacsu, AmableThe work presented here uses Monte Carlo random sampling combined with flux balance analysis and linear programming to analyse the steady-state flux distributions on the surface of the glucose-ammonia phenotypic phase plane of an Escherichia coli system grown oil glucose-minimal medium. The distribution of allowable glucose and ammonia uptake rates showed a triangular shape, the apex corresponding to maximum growth rate. The exact shape, e.g. the diagonal boundary is determined by the relative amounts of nutrients required for growth. The logarithm of flux values has a normal distribution, e.g. there is a log normal distribution, and most of the reactions have an order of magnitude between 10(-1) and 1. The increase in the number of blocked reactions as growth switched from aerobic to micro-aerobic phase and the presence of alternate networks for a single optimal solution were both reflections of the variability of pathway utilization for survival and growth. Principal component analysis (PCA) provided us with significant clues on the correlations between individual reactions and correlations between sets of reactions. Furthermore, PCA identified the most influential reactions of the system. The PCA score plots clearly distinguish two different growth phases, micro-aerobic and aerobic. The loading plots for each growth phase showed both the impact of the reactions on the model and the clustering of reactions that are highly correlated. These results have proved that PCA is a promising way to analyse correlations in high-dimensional solution spaces and to detect modular patterns among reactions in a network. (c) 2006 Elsevier Ltd. All rights reserved.Publication Open Access A review on the mechanistic details of OXA enzymes of ESKAPE pathogens(2023-01-01) SARIYAR AKBULUT, BERNA; ÖZBEK SARICA, PEMRA; Avci F. G., Tastekil I., Jaisi A., ÖZBEK SARICA P., SARIYAR AKBULUT B.The production of beta-lactamases is a prevalent mechanism that poses serious pressure on the control of bacterial resistance. Furthermore, the unavoidable and alarming increase in the transmission of bacteria producing extended-spectrum beta-lactamases complicates treatment alternatives with existing drugs and/or approaches. Class D beta-lactamases, designated as OXA enzymes, are characterized by their activity specifically towards oxacillins. They are widely distributed among the ESKAPE bugs that are associated with antibiotic resistance and life-threatening hospital infections. The inadequacy of current beta-lactamase inhibitors for conventional treatments of \"OXA\" mediated infections confirms the necessity of new approaches. Here, the focus is on the mechanistic details of OXA-10, OXA-23, and OXA-48, commonly found in highly virulent and antibiotic-resistant pathogens Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter spp. to describe their similarities and differences. Furthermore, this review contains a specific emphasis on structural and computational perspectives, which will be valuable to guide efforts in the design/discovery of a common single-molecule drug against ESKAPE pathogens.Publication Open Access An evolutionarily conserved allosteric site modulates beta-lactamase activity(TAYLOR & FRANCIS LTD, 2016-11-03) SARIYAR AKBULUT, BERNA; Avci, Fatma Gizem; Altinisik, Fatma Ece; Vardar Ulu, Didem; Ozkirimli Olmez, Elif; Akbulut, Berna SariyarDeclining efficiency of antibiotic-inhibitor combinatorial therapies in treating beta-lactamase mediated resistance necessitates novel inhibitor development. Allosteric inhibition offers an alternative to conventional drugs that target the conserved active site. Here, we show that the evolutionarily conserved PWP triad located at the N-terminus of the H10 helix directly interacts with the allosteric site in TEM-1 beta-lactamase and regulates its activity. While point mutations in the PWP triad preserve the overall secondary structures around the allosteric site, they result in a more open and dynamic global structure with decreased chemical stability and increased aggregation propensity. These mutant enzymes with a less compact hydrophobic core around the allosteric site displayed significant activity loss. Detailed sequence and structure conservation analyses revealed that the PWP triad is an evolutionarily conserved motif unique to class A beta-lactamases aligning its allosteric site and hence is an effective potential target for enzyme regulation and selective drug design.Publication Metadata only Cellular distribution of activity for three enzymes with maltose binding protein as fusion partner and the structural implications(SCIENTIFIC TECHNICAL RESEARCH COUNCIL TURKEY-TUBITAK, 2010) SARIYAR AKBULUT, BERNA; Utkur, Ozde F.; Akbulut, Berna Sariyar; Hortacsu, AmableThe bacterial SEC pathway is commonly used for secretion of heterologous proteins in E. coli by fusing them to transported proteins to facilitate downstream processing. While some proteins are translocated very efficiently, some reside in the cytoplasm. In this work, maltose binding protein (MBP) was fused to 3 cytoplamic enzymes from Thermus thermophilus (serine protease, 251 residues; glucose isomerase, 381 residues; pullulanase, 718 residues) to study the protein transport from the cytoplasm by quantifying the distribution of activities in different cellular compartments. Pullulanase activity was harvested exclusively in the periplasm; however, glucose isomerase activity was harvested exclusively in the cytoplasm. Considerable serine protease activity was found in the periplasm, but after 10 h of induction activity dropped sharply and no activity was found thereafter in either compartment. This was attributed to the instability of the plasmid probably caused by the proteolytic activity of the protease Computations of hypothetical folding rates and secondary structure contents of the proteins showed that folding rates, in addition to alpha-helix and beta-sheet contents of proteins, could be important determinants for efficient translocation by the SEC pathway. These results may give clues to predict whether a protein would be a suitable fusion tail for periplasmic transport with MBP.Publication Metadata only Assessment of Berberine as a Multi-target Antimicrobial: A Multi-omics Study for Drug Discovery and Repositioning(MARY ANN LIEBERT, INC, 2014) SARIYAR AKBULUT, BERNA; Karaosmanoglu, Kubra; Sayar, Nihat Alpagu; Kurnaz, Isil Aksan; Akbulut, Berna SariyarPostgenomics drug development is undergoing major transformation in the age of multi-omics studies and drug repositioning. Rather than applications solely in personalized medicine, omics science thus additionally offers a better understanding of a broader range of drug targets and drug repositioning. Berberine is an isoquinoline alkaloid found in many medicinal plants. We report here a whole genome microarray study in tandem with proteomics techniques for mining the plethora of targets that are putatively involved in the antimicrobial activity of berberine against Escherichia coli. We found DNA replication/repair and transcription to be triggered by berberine, indicating that nucleic acids, in general, are among its targets. Our combined transcriptomics and proteomics multi-omics findings underscore that, in the presence of berberine, cell wall or cell membrane transport and motility-related functions are also specifically regulated. We further report a general decline in metabolism, as seen by repression of genes in carbohydrate and amino acid metabolism, energy production, and conversion. An involvement of multidrug efflux pumps, as well as reduced membrane permeability for developing resistance against berberine in E. coli was noted. Collectively, these findings offer original and significant leads for omics-guided drug discovery and future repositioning approaches in the postgenomics era, using berberine as a multi-omics case study.