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 Retro-techno-economic evaluation of acetic acid production using cotton stalk as feedstock(SPRINGER, 2018) SAYAR, AHMET ALP; Sayar, Nihat Alpagu; Kazan, Dilek; Pinar, Orkun; Akbulut, Berna Sariyar; Sayar, Ahmet AlpIn value-added chemical industries, use of agricultural wastes as raw materials remains to be a major challenge in commercialization due to lack of competitiveness with respect to petrochemical processes. This work presents the techno-economic analysis of a novel bioprocessing plant converting 356,400MT/year cotton stalks into 147,000MT/year acetic acid. A production scheme integrating lignin separation with the main bioconversion stages has been proposed. Techno-economic assessment was performed through economic feasibility and retro-techno-economic analysis (RTEA) methods. The RTEA method has been extended to include the estimation of research and development funding for improving economic feasibility. Carbon offset of the proposed technology has been estimated and carbon credit results have been incorporated into the economic feasibility metrics.Publication Metadata only pVEC hydrophobic N-terminus is critical for antibacterial activity(WILEY, 2018) SARIYAR AKBULUT, BERNA; Alaybeyoglu, Begum; Akbulut, Berna Sariyar; Ozkirimli, ElifCell-penetrating peptides (CPPs) are commonly defined by their shared ability to be internalized into eukaryotic cells, without inducing permanent membrane damage, and to improve cargo delivery. Many CPPs also possess antimicrobial action strong enough to selectively lyse microbes in infected mammalian cultures. pVEC, a CPP derived from cadherin, is able to translocate into mammalian cells, and it is also antimicrobial. Structure-activity relationship and sequence alignment studies have suggested that the hydrophobic N-terminus (LLIIL) of pVEC is essential for this peptide's uptake into eukaryotic cells. In this study, our aim was to examine the contribution of these residues to the antimicrobial action and the translocation mechanism of pVEC. We performed antimicrobial activity and microscopy experiments with pVEC and with del5 pVEC (N-terminal truncated variant of pVEC) and showed that pVEC loses its antimicrobial effect upon deletion of the LLIIL residues, even though both peptides induce membrane permeability. We also calculated the free energy of the transport process using steered molecular dynamic simulations and replica exchange umbrella sampling simulations to compare the difference in uptake mechanism of the 2 peptides in atomistic detail. Despite the difference in experimentally observed antimicrobial activity, the simulations on the 2 peptides showed similar characteristics and the energetic cost of translocation of pVEC was higher than that of del5 pVEC, suggesting that pVEC uptake mechanism cannot be explained by simple passive transport. Our results suggest that LLIIL residues are key contributors to pVEC antibacterial activity because of irreversible membrane disruption.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 Metadata only Proteomic insight into phenolic adaptation of a moderately halophilic Halomonas sp. strain AAD12(2011) SARIYAR AKBULUT, BERNA; Ceylan, Selim; Akbulut, Berna Sariyar; Denizci, Aziz Akin; Kazan, DilekA gram-negative, moderately halophilic bacterium was isolated from Çamaltı Saltern area, located in the Aegean Region of Turkey. Analysis of its 16S rRNA gene sequence and physiological characteristics showed that this strain belonged to the genus Halomonas ; hence, it was designated as Halomonas sp. strain AAD12. The isolate tolerated up to 800 mg⋅L(-1) phenol; however, at elevated concentrations, phenol severely retarded cell growth. The increase in lag phase with increasing phenol concentrations indicated that the microorganism was undergoing serious adaptative changes. To understand the physiological responses of Halomonas sp. strain AAD12 to phenol, a 2-dimensional electrophoresis approach combined with mass spectrometric analysis was used. This approach showed that the expression of 14 protein spots were altered as phenol concentration increased from 200 to 800 mg⋅L(-1). Among the identified proteins were those involved in protein biosynthesis, energy, transport, and stress metabolism. So far, this is the first study on phenolic adaptation of a gram-negative, moderately halophilic bacteria using proteomic tools. The results provided new insights for understanding the general mechanism used by moderately halophilic bacteria to tolerate phenol and suggested the potential for using these microorganisms in bioremediation.Publication Metadata only A novel chimeric peptide with antimicrobial activity(WILEY, 2015) SARIYAR AKBULUT, BERNA; Alaybeyoglu, Begum; Sariyar Akbulut, Berna; Ozkirimli, ElifBeta-lactamase-mediated bacterial drug resistance exacerbates the prognosis of infectious diseases, which are sometimes treated with co-administration of beta-lactam type antibiotics and beta-lactamase inhibitors. Antimicrobial peptides are promising broad-spectrum alternatives to conventional antibiotics in this era of evolving bacterial resistance. Peptides based on the Ala46-Tyr51 beta-hairpin loop of beta-lactamase inhibitory protein (BLIP) have been previously shown to inhibit beta-lactamase. Here, our goal was to modify this peptide for improved beta-lactamase inhibition and cellular uptake. Motivated by the cell-penetrating pVEC sequence, which includes a hydrophobic stretch at its N-terminus, our approach involved the addition of LLIIL residues to the inhibitory peptide N-terminus to facilitate uptake. Activity measurements of the peptide based on the 45-53 loop of BLIP for enhanced inhibition verified that the peptide was a competitive beta-lactamase inhibitor with a K-i value of 58M. Incubation of beta-lactam-resistant cells with peptide decreased the number of viable cells, while it had no effect on beta-lactamase-free cells, indicating that this peptide had antimicrobial activity via beta-lactamase inhibition. To elucidate the molecular mechanism by which this peptide moves across the membrane, steered molecular dynamics simulations were carried out. We propose that addition of hydrophobic residues to the N-terminus of the peptide affords a promising strategy in the design of novel antimicrobial peptides not only against beta-lactamase but also for other intracellular targets. Copyright (c) 2015 European Peptide Society and John Wiley & Sons, Ltd.Publication Metadata only Proteomic response of Escherichia coli to the alkaloid extract of Papaver polychaetum(SPRINGER, 2010) SARIYAR AKBULUT, BERNA; Ozbalci, Cagakan; Unsal, Caglayan; Kazan, Dilek; Sariyar-Akbulut, BernaThe cellular response of Escherichia coli exposed to alkaloids extracted from a biennial endemic plant, Papaver polychaetum, was explored using proteome analysis. Following determination of the minimum inhibitory concentration of the berberine-containing plant extract as 1,250 mu g/mL, E. coli cells were grown in the presence of 750 mu g/mL extract. The response of the bacteria to the extract, with berberine found as the major alkaloid, was analyzed on two-dimensional gels. The differentially expressed proteins in the presence of 750 mu g/mL extract were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. These proteins included those that play vital roles for maintenance such as protein synthesis (elongation factor-Ts), transport (oligopeptide-binding protein A, uncharacterized amino-acid ABC transporter ATP binding protein YECC), energy metabolism (alpha-subunit of ATP synthase, pyridine nucleotide transhydrogenase STHA) and regulation. These results provide clues for understanding the mechanism of the alkaloid extract-induced stress and cytotoxicity on E. coli. The altered proteins can serve as potential targets for development of innovative therapeutic agents.Publication Metadata only Transcriptomic analysis displays the effect of (-)-roemerine on the motility and nutrient uptake in Escherichia coli(SPRINGER, 2017) SARIYAR AKBULUT, BERNA; Ayyildiz, Dilara; Arga, Kazim Yalcin; Avci, Fatma Gizem; Altinisik, Fatma Ece; Gurer, Caglayan; Toplan, Gizem Gulsoy; Kazan, Dilek; Wozny, Katharina; Bruegger, Britta; Mertoglu, Bulent; Akbulut, Berna SariyarAmong the different families of plant alkaloids, (-)-roemerine, an aporphine type, was recently shown to possess significant antibacterial activity in Escherichia coli. Based on the increasing demand for antibacterials with novel mechanisms of action, the present work investigates the potential of the plant-derived alkaloid (-)-roemerine as an antibacterial in E. coli cells using microarray technology. Analysis of the genome-wide transcriptional reprogramming in cells after 60 min treatment with 100 mu g/mL (-)-roemerine showed significant changes in the expression of 241 genes (p value < 0.05 and fold change > 2). Expression of selected genes was confirmed by qPCR. Differentially expressed genes were classified into functional categories to map biological processes and molecular pathways involved. Cellular activities with roles in carbohydrate transport and metabolism, energy production and conversion, lipid transport and metabolism, amino acid transport and metabolism, two-component signaling systems, and cell motility (in particular, the flagellar organization and motility) were among metabolic processes altered in the presence of (-)-roemerine. The down-regulation of the outer membrane proteins probably led to a decrease in carbohydrate uptake rate, which in turn results in nutrient limitation. Consequently, energy metabolism is slowed down. Interestingly, the majority of the expressional alterations were found in the flagellar system. This suggested reduction in motility and loss in the ability to form biofilms, thus affecting protection of E. coli against host cell defense mechanisms. In summary, our findings suggest that the antimicrobial action of (-)-roemerine in E. coli is linked to disturbances in motility and nutrient uptake.Publication Metadata only Proteomics in industrial biotechnology(CURRENT BIOLOGY LTD, 2011) SARIYAR AKBULUT, BERNA; Ceylan, Selim; Ozbalci, Cagakan; Akbulut, Berna Sariyar; Kazan, DilekPublication Metadata only Insights into membrane translocation of the cell-penetrating peptide pVEC from molecular dynamics calculations(TAYLOR & FRANCIS INC, 2016) SARIYAR AKBULUT, BERNA; Alaybeyoglu, Begum; Akbulut, Berna Sariyar; Ozkirimli, ElifDiscovery of cargo carrying cell-penetrating peptides has opened a new gate in the development of peptide-based drugs that can effectively target intracellular enzymes. Success in application and development of cell-penetrating peptides in drug design depends on understanding their translocation mechanisms. In this study, our aim was to examine the bacterial translocation mechanism of the cell-penetrating pVEC peptide (LLIILRRRIRKQAHAHSK) using steered molecular dynamics (SMD) simulations. The significance of specific residues or regions for translocation was studied by performing SMD simulations on the alanine mutants and other variants of pVEC. Residue-based analysis showed that positively charged residues contribute to adsorption to the lipid bilayer and to electrostatic interactions with the lipid bilayer as peptides are translocated. Translocation takes place in three main stages; the insertion of the N-terminus into the bilayer, the inclusion of the whole peptide inside the membrane and the exit of the N-terminus from the bilayer. These three stages mirror the three regions on pVEC; namely, the hydrophobic N-terminus, the cationic midsection, and the hydrophilic C-terminus. The N-terminal truncated pVEC, I3A, L5A, R7A mutants and scramble-pVEC make weaker interactions with the lipids during translocation highlighting the contribution of the N-terminal residues and the sequence of the structural regions to the translocation mechanism. This study provides atomistic detail about the mechanism of pVEC peptide translocation and can guide future peptide-based drug design efforts.