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 What Are the Multi-Omics Mechanisms for Adaptation by Microorganisms to High Alkalinity? A Transcriptomic and Proteomic Study of a Bacillus Strain with Industrial Potential(MARY ANN LIEBERT, INC, 2018) SAYAR, AHMET ALP; Kaya, Fatma Ece Altinisik; Avci, Fatma Gizem; Sayar, Nihat Alpagu; Kazan, Dilek; Sayar, Ahmet Alp; Akbulut, Berna SariyarAlkaliphilic organisms are among an industrially important class of extremophile microorganisms with the ability to thrive at pH 10-11.5. Microorganisms that exhibit alkaliphilic characteristics are sources of alkali-tolerant enzymes such as proteases, starch degrading enzymes, cellulases, and metabolites such as antibiotics, enzyme inhibitors, siderophores, organic acids, and cholic acid derivatives, which have found various applications in industry for human and environmental health. Yet, multi-omics mechanisms governing adaptation to high alkalinity have been poorly studied. We undertook the present work to understand, as a case study, the alkaliphilic adaptation strategy of the novel microorganism, Bacillus marmarensis DSM 21297, to alkaline conditions using a multi-omics approach that employed transcriptomics and proteomics. As alkalinity increased, bacteria remodeled the peptidoglycan layer by changing peptide moieties along with the peptidoglycan constituents and altered the cell membrane to reduce lipid motility and proton leakiness to adjust intracellular pH. Different transporters also contributed to the maintenance of this pH homeostasis. However, unlike in most well-known alkaliphiles, not only sodium ions but also potassium ions were involved in this process. Interestingly, increased pH has triggered the expression of neither general stress proteins nor gene encoding proteins associated with heat, salt, and nutrient stresses. Only an increase in the expression of oxidative stress related genes was evident. Endospore formation, also a phenomenon closely linked to stress, was unclear. This questioned if high pH was a real stress for B. marmarensis. These new findings, corroborated using the multi-omics approach of the present case study, broaden the knowledge on the mechanisms of alkaliphilic adaptation and might also potentially offer useful departure points for further industrial applications with other microorganisms.Publication Metadata only Targeting a hidden site on class A beta-lactamases(ELSEVIER SCIENCE INC, 2018) SARIYAR AKBULUT, BERNA; Avci, Fatma Gizem; Altinisik, Fatma Ece; Karacan, Ipek; Karagoz, Duygu Senturk; Ersahin, Serhat; Eren, Ayse; Sayar, Nihat Alpagu; Ulu, Didem Vardar; Ozkirimli, Elif; Akbulut, Berna SariyarIncreasing resistance against available orthosteric beta-lactamase inhibitors necessitates the search for novel and powerful inhibitor molecules. In this respect, allosteric inhibitors serve as attractive alternatives. Here, we examine the structural basis of inhibition in a hidden, druggable pocket in TEM-1 betalactamase. Based on crystallographic evidence that 6-cyclohexyl-1-hexyl-beta-D-maltoside (CYMAL-6) binds to this site, first we determined the kinetic mechanism of inhibition by CYMAL-6. Activity measurements with CYMAL-6 showed that it competitively inhibits the wild type enzyme. Interestingly, it exhibits a steep dose -response curve with an IC50 of 100 mu M. The IC50 value changes neither with different enzyme concentration nor with incubation of the enzyme with the inhibitor, showing that inhibition is not aggregation -based. The presence of the same concentrations of CYMAL-6 does not influence the activity of lactate dehydrogenase, further confirming the specificity of CYMAL-6 for TEM-1 beta-lactamase. Then, we identified compounds with high affinity to this allosteric site by virtual screening using Glide and Schrodinger Suite. Virtual screening performed with 500,000 drug like compounds from the ZINC database showed that top scoring compounds interact with the hydrophobic pocket that forms between H10 and Hll helices and with the catalytically important Arg244 residue through pi -cation interactions. Discovery of novel chemical scaffolds that target this allosteric site will pave the way for a new avenue in the design of new antimicrobials. (C) 2018 Elsevier Inc. All rights reserved.Publication Metadata only Techno-economic analysis of caffeine and catechins production from black tea waste(ELSEVIER, 2019) SARIYAR AKBULUT, BERNA; Sayar, Nihat Alpagu; Sam, Selcen Durmaz; Pinar, Orkun; Serper, Damla; Akbulut, Berna Sanyar; Kazan, Dilek; Sayar, Ahmet Alpy This work establishes a proof of concept level economic assessment of a novel commercial production scheme for caffeine and catechins from black tea waste collected in the north-eastern region of Turkey. A base case in which dichloromethane (DCM) is used as the product extracting agent and an alternative greener case where DCM is replaced with environmentally friendlier ethyl acetate (EA) were designed and modelled on Superpro Designer platform. Profitability analyses were conducted for both cases, each treating 30,000 MT/year of black tea waste. Under the base case scenario, the Net Present Value (NPV) was calculated as 16,249,000 USD whereas the alternative scenario gave an NPV of 4,379,000 USD with corresponding payback times of 5.64 and 6.79 years. A novel techno-economic evaluation method involving the metamodeling of Superpro Designer models via Kriging and subsequent multi-objective optimization is incorporated into the economic assessment and applied to the two cases in order to optimize selected dominant process variables. Optimal values for dominant operating process variables were found using 3-D graphs simulating the combined effects of these variables on NPV. Results showed that the base case has a greater potentiality to generate profit. However, the greener case could be implemented if it is supported on environmental and toxicity issues considering the potential health and pollution preventive benefits. The present work demonstrates how the integration of novel conceptual design, modelling, and optimization approaches can foster broader evaluation of bioprocesses utilizing negative-value agro-wastes for the production of value-added chemicals. (C) 2019 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.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 Metadata only Response of Escherichia coli to Prolonged Berberine Exposure(MARY ANN LIEBERT, INC, 2017) SARIYAR AKBULUT, BERNA; Gokgoz, Nilay Budeyri; Avci, Fatma Gizem; Yoneten, Kubra Karaosmanoglu; Alaybeyoglu, Begum; Ozkirimli, Elif; Sayar, Nihat Alpagu; Kazan, Dilek; Akbulut, Berna SariyarBerberine is a plant-derived alkaloid possessing antimicrobial activity; unfortunately, its efflux through multidrug resistance pumps reduces its efficacy. Cellular life span of Escherichia coli is generally shorter with prolonged berberine exposure; nevertheless, about 30% of the cells still remain robust following this treatment. To elucidate its mechanism of action and to identify proteins that could be involved in development of antimicrobial resistance, protein profiles of E. coli cells treated with berberine for 4.5 and 8 hours were compared with control cells. A total of 42 proteins were differentially expressed in cells treated with berberine for 8 hours when compared to control cells. In both 4.5 and 8 hours of berberine-treated cells, carbohydrate and peptide uptake regimens remained unchanged, although amino acid maintenance regimen switched from transport to synthesis. Defect in cell division persisted and this condition was confirmed by images obtained from scanning electron microscopy. Universal stress proteins were not involved in stress response. The significant increase in the abundance of elongation factors could suggest the involvement of these proteins in protection by exhibiting chaperone activities. Furthermore, the involvement of the outer membrane protein OmpW could receive special attention as a protein involved in response to antimicrobial agents, since the expression of only this porin protein was upregulated after 8 hours of exposure.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.Publication Metadata only An OMIC approach to elaborate the antibacterial mechanisms of different alkaloids(PERGAMON-ELSEVIER SCIENCE LTD, 2018) SARIYAR AKBULUT, BERNA; Avci, Fatma Gizem; Sayar, Nihat Alpagu; Akbulut, Berna SariyarPlant-derived substances have regained interest in the fight against antibiotic resistance owing to their distinct antimicrobial mechanisms and multi-target properties. With the recent advances in instrumentation and analysis techniques, OMIC approaches are extensively used for target identification and elucidation of the mechanism of phytochemicals in drug discovery. In the current study, RNA sequencing based transcriptional profiling together with global differential protein expression analysis was used to comparatively elaborate the activities and the effects of the plant alkaloids boldine, bulbocapnine, and roemerine along with the well-known antimicrobial alkaloid berberine in Bacillus subtilis cells. The transcriptomic findings were validated by qPCR. Images from scanning electron microscope were obtained to visualize the effects on the whole-cells. The results showed that among the three selected alkaloids, only roemerine possessed antibacterial activity. Unlike berberine, which is susceptible to efflux through multidrug resistance pumps, roemerine accumulated in the cells. This in turn resulted in oxidative stress and building up of reactive oxygen species, which eventually deregulated various pathways such as iron uptake. Treatment with boldine or bulbocapnine slightly affected various metabolic pathways but has not changed the growth patterns at all. (C) 2018 Elsevier Ltd. All rights reserved.