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Al Bratty, Mohammed, Ayman Q. Hakami, Hatim A. Masmali, Md Shamsher Alam, Hassan A. Alhazmi, Neelaveni Thangavel, Asim Najmi, Sivakumar S. Moni, and Anzarul Haque. "The Spectrum of Thiazolidinediones against Respiratory Tract Pathogenic Bacteria: An In Vitro and In Silico Approach." Current Pharmaceutical Biotechnology 21, no. 14 (December 7, 2020): 1457–69. http://dx.doi.org/10.2174/1389201021666200618161210.
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Background and Objectives: Drug design strategies to develop novel broad-spectrum antibacterial agents for the treatment of respiratory tract infections that can combat bacterial resistance are currently gaining momentum. 2,4-thiazolidinedione is a structural scaffold that contains pharmacophores similar to β-lactam and non- β-lactam antibiotics. The objective of the study was to synthesize newer 3,5-Disubstituted-2,4-Thiazolidinediones (DTZDs) and subject them to in vitro antibacterial screening against bacterial pathogens. Also, we performed in silico docking of selected compounds to penicillin-binding proteins and beta-lactamases. Methods: Intermediate Schiff bases were prepared by the reaction between 2,4-thiazolidinedione and an appropriate aldehyde followed by acylation of the ring nitrogen with 3-brompropanoyl chloride resulting in DTZDs. Minimum inhibitory concentrations were determined against few bacteria infecting the respiratory tract by the broth tube dilution method. Zones of inhibitions against the bacteria were also determined using agar well diffusion technique. Molecular docking of the compounds to all types of Penicillin-Binding Proteins (PBPs) and β-lactamases was also carried out. Results: Compounds DTZD12 and DTZD16 exhibited broad-spectrum antibacterial activity. The minimum inhibitory concentrations of the compounds were 175μg/100μL. Measurements of the zones of inhibitions indicated that compound DTZD12 was more active than DZTD16. E. coli was the most susceptible organism. Docking results established that both the compounds were able to interact with PBPs and β-lactamases through strong hydrogen bonds, especially the unique interaction with active serine residue of the PBP for inhibition of cell wall synthesis. Conclusion: DTZD12 and DTZD16 can be developed into antibacterial drugs for respiratory tract infections to oppose bacterial resistance, or can also be used as leads for repurposing the existing 2,4- thiazolidinediones.
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Klein, Ronald D., and Timothy G. Geary. "Recombinant Microorganisms as Tools for High Throughput Screening for Nonantibiotic Compounds." Journal of Biomolecular Screening 2, no. 1 (February 1997): 41–49. http://dx.doi.org/10.1177/108705719700200108.
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Microorganisms were among the first tools used for the discovery of biologically active compounds. Their utility reached a zenith during the era of antibiotic development in the 1950s and 1960s, then declined. Subsequently, a substantial role for microorganisms in the pharmaceutical industry developed with the realization that microbial fermentations were intriguing sources of nonantibiotic natural products. From recombinant DNA technology emerged another important role for microorganisms in pharmaceutical research: the expression of heterologous proteins for therapeutic products or for in vitro high throughput screens (HTSs). Recent developments in cloning, genetics, and expression systems have opened up new applications for recombinant microorganisms in screening for nonantibiotic compounds in HTSs. These screens employ microorganisms that depend upon the function of a heterologous protein for survival under defined nutritional conditions. Compounds that specifically target the heterologous protein can be identified by measuring viability of the microorganism under different nutrient selection. Advantages of this approach include a built-in selection for target selectivity, an easily measured end point that can be used for a multitude of different targets, and compatibility with automation required for HTSs. Mechanism-based HTSs using recombinant microorganisms can also address drug targets that are not readily approachable in other HTS formats, including certain enzymes; ion channels and transporters; and protein::protein, protein::DNA, and protein::RNA interactions.
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Winther, Tabita, and Lene Oddershede. "Effect of Antibiotics and Antimicrobial Peptides on Single Protein Motility." Current Pharmaceutical Biotechnology 10, no. 5 (August 1, 2009): 486–93. http://dx.doi.org/10.2174/138920109788922083.
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Tabassum Samanta, Mahonaz, and Sadia Noor. "PROSPECTS AND CHALLENGES OF PHARMACEUTICAL BIOTECHNOLOGY." International Journal of Advanced Research 9, no. 01 (January 31, 2021): 709–29. http://dx.doi.org/10.21474/ijar01/12349.
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Biotechnology is a broad area of biology, involving the use of living systems and organisms to develop products. Depending on the tools and applications, it often overlaps with related scientific fields. In the late 20th and early 21st centuries, biotechnology has expanded to include new and diverse sciences, such as genomics, recombinant gene techniques, applied immunology, and development of pharmaceutical therapies and diagnostic tests. Biotechnology has also led to the development of antibiotics. Biotechnology has applications in four major industrial areas, including health care (medical), crop production and agriculture, non-food (industrial) uses of crops and other products and environmental uses. In medicine, modern biotechnology has many applications in areas such as pharmaceutical drug discoveries and production, pharmacogenomics, and genetic testing. Pharmaceutical biotechnology is a relatively new and growing field in which the principles of biotechnology are applied to the development of drugs. A majority of therapeutic drugs in the current market are bio formulations, such as antibodies, nucleic acid products and vaccines. Such bio formulations are developed through several stages that include: understanding the principles underlying health and disease the fundamental molecular mechanisms governing the function of related biomolecules synthesis and purification of the molecules determining the product shelf life, stability, toxicity and immunogenicity drug delivery systems patenting and clinical trials. This review article describes the purpose of biotechnology in pharmaceutical industry, particularly pharmaceutical biotechnology along with its prospects and challenges.
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Cobos-Puc, Luis, Raúl Rodríguez-Herrera, Juan C. Cano-Cabrera, Hilda Aguayo-Morales, Sonia Y. Silva-Belmares, Adriana C. F. Gallegos, and José L. M. Hernández. "Classical and New Pharmaceutical Uses of Bacterial Penicillin G Acylase." Current Pharmaceutical Biotechnology 21, no. 4 (March 25, 2020): 287–97. http://dx.doi.org/10.2174/1389201020666191111151642.
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Background: β-lactam antibiotics are the most used worldwide for the treatment of bacterial infections. The consumption of these classes of drugs is high, and it is increasing around the world. To date, the best way to produce them is using penicillin G Acylase (PGA) as a biocatalyst. Objective: This manuscript offers an overview of the most recent advances in the current tools to improve the activity of the PGA and its pharmaceutical application. Results: Several microorganisms produce PGA, but some bacterial strains represent the primary source of this enzyme. The activity of bacterial PGA depends on its adequate expression and carbon or nitrogen source, as well as a specific pH or temperature depending on the nature of the PGA. Additionally, the PGA activity can be enhanced by immobilizing it to a solid support to recycle it for a prolonged time. Likewise, PGAs more stable and with higher activity are obtained from bacterial hosts genetically modified. Conclusion: PGA is used to produce b-lactam antibiotics. However, this enzyme has pharmaceutical potential to be used to obtain critical molecules for the synthesis of anti-tumor, antiplatelet, antiemetic, antidepressive, anti-retroviral, antioxidant, and antimutagenic drugs.
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Potocki, Leszek, Bernadetta Oklejewicz, Ewelina Kuna, Ewa Szpyrka, Magdalena Duda, and Janusz Zuczek. "Application of Green Algal Planktochlorella nurekis Biomasses to Modulate Growth of Selected Microbial Species." Molecules 26, no. 13 (July 1, 2021): 4038. http://dx.doi.org/10.3390/molecules26134038.
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As microalgae are producers of proteins, lipids, polysaccharides, pigments, vitamins and unique secondary metabolites, microalgal biotechnology has gained attention in recent decades. Microalgae can be used for biomass production and to obtain biotechnologically important products. Here, we present the application of a method of producing a natural, biologically active composite obtained from unicellular microalgae of the genus Planktochlorella sp. as a modulator of the growth of microorganisms that can be used in the cosmetics and pharmaceutical industries by exploiting the phenomenon of photo-reprogramming of metabolism. The combination of red and blue light allows the collection of biomass with unique biochemical profiles, especially fatty acid composition (Patent Application P.429620). The ethanolic and water extracts of algae biomass inhibited the growth of a number of pathogenic bacteria, namely Enterococcus faecalis, Staphylococcus aureus PCM 458, Streptococcus pyogenes PCM 2318, Pseudomonas aeruginosa, Escherichia coli PCM 2209 and Candida albicans ATCC 14053. The algal biocomposite obtained according to our procedure can be used also as a prebiotic supplement. The presented technology may allow the limitation of the use of antibiotics and environmentally harmful chemicals commonly used in preparations against Enterococcus faecalis, Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa, Escherichia coli or Candida spp.
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Messaoudi, Abdelmonaem, Manel Zoghlami, Zarrin Basharat, and Najla Sadfi-Zouaoui. "Identification of a Potential Inhibitor Targeting MurC Ligase of the Drug Resistant Pseudomonas aeruginosa Strain through Structure-Based Virtual Screening Approach and In Vitro Assay." Current Pharmaceutical Biotechnology 20, no. 14 (November 15, 2019): 1203–12. http://dx.doi.org/10.2174/1389201020666190719123133.
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Background & Objective: Pseudomonas aeruginosa shows resistance to a large number of antibiotics, including carbapenems and third generation cephalosporin. According to the World Health Organization global report published in February 2017, Pseudomonas aeruginosa is on the priority list among resistant bacteria, for which new antibiotics are urgently needed. Peptidoglycan serves as a good target for the discovery of novel antimicrobial drugs. Methods: Biosynthesis of peptidoglycan is a multi-step process involving four mur enzymes. Among these enzymes, UDP-N-acetylmuramate-L-alanine ligase (MurC) is considered to be an excellent target for the design of new classes of antimicrobial inhibitors in gram-negative bacteria. Results: In this study, a homology model of Pseudomonas aeruginosa MurC ligase was generated and used for virtual screening of chemical compounds from the ZINC Database. The best screened inhibitor i.e. N, N-dimethyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-sulfonamide was then validated experimentally through inhibition assay. Conclusion: The presented results based on combined computational and in vitro analysis open up new horizons for the development of novel antimicrobials against this pathogen.
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Osa-Andrews, Bremansu, Kee Tan, Angelina Sampson, and Surtaj Iram. "Development of Novel Intramolecular FRET-Based ABC Transporter Biosensors to Identify New Substrates and Modulators." Pharmaceutics 10, no. 4 (October 13, 2018): 186. http://dx.doi.org/10.3390/pharmaceutics10040186.
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Multidrug resistance protein 1 (MRP1) can efflux a wide variety of molecules including toxic chemicals, drugs, and their derivatives out of cells. Substrates of MRP1 include anti-cancer agents, antibiotics, anti-virals, anti-human immunodeficiency virus (HIV), and many other drugs. To identify novel substrates and modulators of MRP1 by exploiting intramolecular fluorescence resonance energy transfer (FRET), we genetically engineered six different two-color MRP1 proteins by changing green fluorescent protein (GFP) insertion sites, while keeping the red fluorescent protein (RFP) at the C-terminal of MRP1. Four of six recombinant proteins showed normal expression, localization, and transport activity. We quantified intramolecular FRET using ensemble fluorescence spectroscopy in response to binding of known substrate or ATP alone, substrate/ATP, and trapping of the transporter in closed conformation by vanadate. Recombinant MRP1 proteins GR-881, GR-888, and GR-905 exhibited reproducible and higher FRET changes under all tested conditions and are very promising for use as MRP1 biosensors. Furthermore, we used GR-881 to screen 40 novel anti-cancer drugs and identified 10 hits that potentially directly interact with MRP1 and could be substrates or modulators. Profiling of drug libraries for interaction with MRP1 can provide very useful information to improve the efficacy and reduce the toxicity of various therapies.
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Keskar, Mrudul R., and Ravin M. Jugade. "Spectrophotometric Investigations of Macrolide Antibiotics: A Brief Review." Analytical Chemistry Insights 10 (January 2015): ACI.S31857. http://dx.doi.org/10.4137/aci.s31857.
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Macrolides, one of the most commonly used class of antibiotics, are a group of drugs produced by Streptomyces species. They belong to the polyketide class of natural products. Their activity is due to the presence of a large macrolide lactone ring with deoxy sugar moieties. They are protein synthesis inhibitors and broad-spectrum antibiotics, active against both gram-positive and gram-negative bacteria. Different analytical techniques have been reported for the determination of macrolides such as chromatographic methods, flow injection methods, spectrofluorometric methods, spectrophotometric methods, and capillary electrophoresis methods. Among these methods, spectrophotometric methods are sensitive and cost effective for the analysis of various antibiotics in pharmaceutical formulations as well as biological samples. This article reviews different spectrophotometric methods for the determination of macrolide antibiotics.
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Salmaso, Stefano, Sara Bersani, Alessandra Semenzato, and Paolo Caliceti. "Nanotechnologies in Protein Delivery." Journal of Nanoscience and Nanotechnology 6, no. 9 (September 1, 2006): 2736–53. http://dx.doi.org/10.1166/jnn.2006.456.
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The growth rate for biotech drugs, namely proteins, peptides, and oligonucleotides, is dictated by the parallel progresses in biotechnology and nanotechnology. Actually, biotechnology techniques have expanded enormously the arsenal of therapeutically useful peptides and proteins making these products of primary interest for future pharmaceutical market. Nevertheless, the exploitation of protein and peptide drugs is strictly related to the development of innovative delivery systems which should provide for controlled, prolonged, or targeted delivery, improved stability during storage and delivery, reduced adverse effects, increased bioavailability, improved patient compliance and allow for administration through the desired route and cope with cost-containment therapeutic protocols. Colloidal formulations ideally possess the physicochemical and biopharmaceutical requisites for protein delivery. Pharmaceutical nanotechnology is a tool of techniques applied to design, develop and produce these systems. It involves the investigation of innovative materials and production procedures for preparation of a variety of nanosized dosage forms, which range from solid nanoparticles to soluble bioconjugates. The research and development of innovative tailor made protein delivery systems, which must be designed according to the drug candidate pharmacological and physicochemical properties, is one of the primary aim of modern pharmaceutical technology. Therefore, as an unmet need exists for technologies that combine innovative drug delivery solutions, a close un-prejudicial interaction between academic and industrial researchers as well as business thought leaders is required.
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Wright, Gerard D. "Something old, something new: revisiting natural products in antibiotic drug discovery." Canadian Journal of Microbiology 60, no. 3 (March 2014): 147–54. http://dx.doi.org/10.1139/cjm-2014-0063.
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Antibiotic discovery is in crisis. Despite a growing need for new drugs resulting from the increasing number of multi-antibiotic-resistant pathogens, there have been only a handful of new antibiotics approved for clinical use in the past 2 decades. Faced with scientific, economic, and regulatory challenges, the pharmaceutical sector seems unable to respond to what has been called an “apocalyptic” threat. Natural products produced by bacteria and fungi are genetically encoded products of natural selection that have been the mainstay sources of the antibiotics in current clinical use. The pharmaceutical industry has largely abandoned these compounds in favor of large libraries of synthetic molecules because of difficulties in identifying new natural product antibiotics scaffolds. Advances in next-generation genome sequencing, bioinformatics, and analytical chemistry are combining to overcome barriers to natural products. Coupled with new strategies in antibiotic discovery, including inhibition of resistance, novel drug combinations, and new targets, natural products are poised for a renaissance to address what is a pressing health care crisis.
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Chaulagain, Bivek, Ankit Jain, Ankita Tiwari, Amit Verma, and Sanjay K. Jain. "Passive delivery of protein drugs through transdermal route." Artificial Cells, Nanomedicine, and Biotechnology 46, sup1 (January 29, 2018): 472–87. http://dx.doi.org/10.1080/21691401.2018.1430695.
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Aldosari, Mohammed H., Marcel den Hartog, Hubertina Ganizada, Martijn J. W. Evers, Enrico Mastrobattista, and Huub Schellekens. "Feasibility Study for Bedside Production of Recombinant Human Acid α-Glucosidase: Technical and Financial Considerations." Current Pharmaceutical Biotechnology 21, no. 6 (May 20, 2020): 467–79. http://dx.doi.org/10.2174/1389201021666200217113049.
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Objective: The high cost of orphan drugs limits their access by many patients, especially in low- and middle-income countries. Many orphan drugs are off-patent without alternative generic or biosimilar versions available. Production of these drugs at the point-of-care, when feasible, could be a cost-effective alternative. Methods: The financial feasibility of this approach was estimated by setting up a small-scale production of recombinant human acid alpha-glucosidase (rhGAA). The commercial version of rhGAA is Myozyme™, and Lumizyme™ in the United States, which is used to treat Pompe disease. The rhGAA was produced in CHO-K1 mammalian cells and purified using multiple purification steps to obtain a protein profile comparable to Myozyme™. Results: The established small-scale production of rhGAA was used to obtain a realistic cost estimation for the magistral production of this biological drug. The treatment cost of rhGAA using bedside production was estimated at $3,484/gram, which is 71% lower than the commercial price of Myozyme ™. Conclusion: This study shows that bedside production might be a cost-effective approach to increase the access of patients to particular life-saving drugs.
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Hobden, A. N., and T. J. R. Harris. "The impact of biotechnology and molecular biology on the pharmaceutical industry." Proceedings of the Royal Society of Edinburgh. Section B. Biological Sciences 99, no. 1-2 (1992): 37–45. http://dx.doi.org/10.1017/s0269727000013038.
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Synopsis:Biotechnology had its initial impact on the pharmaceutical industry well before the perceived time. The use of fermentation technology to produce antibiotics was a cornerstone for the development of the industry. This event was both before cloning (BC) and before DNA (rather than after DNA – AD). Even now the antibiotic market, which is worth over 10 billion U.S. dollars a year, is the most valuable segment of the total market, (c.200 billion dollars per year). Nevertheless the impact of biotechnology in drug discovery was until recently perceived solely to be the use of recombinant DNA techniques to produce therapeutic proteins and modified versions of them by protein engineering.There are several other places where genetic engineering is influencing drug discovery. The expression of recombinant proteins in surrogate systems (e.g. in E. coli, yeast or via baculovirus infection or in mammalian cells) provides materials for structure determination (e.g. HIV protease) and structure/function studies (e.g. various receptors). Recombinant DNA techniques are influencing assay technology by allowing access to proteins in sufficient quantity for high throughput screening.In addition, screening organisms can be constructed where a particular protein function can be measured in a microorganism by complementation or via reporter gene expression.Transgenic animals also illustrate the power of the technology for drug discovery. Not only will transgenic rats and mice be used as models of disease but also for efficacy and toxicological profiling. What is learned in transgenic rodents may well set the scene for somatic cell gene therapy in humans.
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Foti, Claudia, Anna Piperno, Angela Scala, and Ottavia Giuffrè. "Oxazolidinone Antibiotics: Chemical, Biological and Analytical Aspects." Molecules 26, no. 14 (July 14, 2021): 4280. http://dx.doi.org/10.3390/molecules26144280.
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This review covers the main aspects concerning the chemistry, the biological activity and the analytical determination of oxazolidinones, the only new class of synthetic antibiotics advanced in clinical use over the past 50 years. They are characterized by a chemical structure including the oxazolidone ring with the S configuration of substituent at C5, the acylaminomethyl group linked to C5 and the N-aryl substituent. The synthesis of oxazolidinones has gained increasing interest due to their unique mechanism of action that assures high antibiotic efficiency and low susceptibility to resistance mechanisms. Here, the main features of oxazolidinone antibiotics licensed or under development, such as Linezolid, Sutezolid, Eperezolid, Radezolid, Contezolid, Posizolid, Tedizolid, Delpazolid and TBI-223, are discussed. As they are protein synthesis inhibitors active against a wide spectrum of multidrug-resistant Gram-positive bacteria, their biological activity is carefully analyzed, together with the drug delivery systems recently developed to overcome the poor oxazolidinone water solubility. Finally, the most employed analytical techniques for oxazolidinone determination in different matrices, such as biological fluids, tissues, drugs and natural waters, are reviewed. Most are based on HPLC (High Performance Liquid Chromatography) coupled with UV-Vis or mass spectrometer detectors, but, to a lesser extent are also based on spectrofluorimetry or voltammetry.
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Paulson, James R., Ibrahim Y. Mahmoud, Salma K. Al-Musharafi, and Saif N. Al-Bahry. "Antibiotic Resistant Bacteria in the Environment as Bio-Indicators of Pollution." Open Biotechnology Journal 10, no. 1 (November 11, 2016): 342–51. http://dx.doi.org/10.2174/1874070701610010342.
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Antibiotic resistant and multiple-antibiotic resistant bacteria (MARB) have become increasingly widespread, primarily due to overuse of antibiotics in clinical therapeutics and in growth promotion for livestock. This undermines the usefulness of the drugs and presents a serious problem for human health. Compounding the problem, resistance determinants can spread between different bacteria via transfer of genetic material, so that the digestive tracts of farm animals, for example, have become breeding grounds for MARB. Antibiotics and resistant bacteria enter the environment in both treated and untreated sewage, via wastewater streams from hospitals and pharmaceutical plants, and through agricultural runoff from feedlots and fields fertilized with manure. This has led to contamination of groundwater, lakes, rivers and coastal sea water, and high levels of MARB in wildlife which indicates pollution of these habitats. Here we propose that the level of antibiotic-resistant bacteria in wildlife, for example sea turtles and fish, could be used as a bioindicator to monitor pollution and to evaluate the success of efforts to curtail it.
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Li, Houli, Xiaoliang Cheng, Di Zhang, Maoyi Wang, Weihua Dong, and Weiyi Feng. "A UPLC-MS/MS Assay for Simultaneous Determination of Two Antipsychotics and Two Antidepressants in Human Plasma and Its Application in Clinic." Current Pharmaceutical Biotechnology 21, no. 1 (January 7, 2020): 60–69. http://dx.doi.org/10.2174/1389201020666190830150549.
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Background: Antidepressants and antipsychotics are widely prescribed drugs for the treatment of mental diseases. Therapeutic drug monitoring (TDM) is recommended for patients taking these drugs to ensure pharmaceutical efficacy, medication compliance and prevent toxicity. Objective: An ultra-high performance liquid chromatography/tandem-mass spectrometry (UPLC-MS/ MS) method was developed for simultaneous determination of two Antidepressants-Fluoxetine (FLU) and Escitalopram (ESC), and two antipsychotics-risperidone (RIS) and aripiprazole (ARI), in human plasma. Methods: The sample was processed by simple protein precipitation and the targeted analytes were separated on a C18 column by gradient elution with a mobile phase containing 0.1% formic acid (v/v) and acetonitrile. All the analytes were qualitative and quantitative measured by electrospray ionization source with Multiple Reaction Monitoring (MRM) in positive ion mode. A total of 56 plasma samples were obtained from out- or in-patients who were taking the cited four drugs for further analysis. Results: The calibration curves for FLU, ESC, RIS and ARI were linear in the range of 45-1800, 4-320, 2-200 and 50-1800 ng/mL, respectively. The entire analytical time for the analytes was 7.0 min for each run and the extraction efficiency was more than 90%. The sample was stable within various storage conditions. The trough concentrations in patients were measured with the validated method. Conclusions: The developed method was successfully used for simultaneous determination of FLU, ESC, RIS and ARI in the plasma of the patients, which provides effective technical support for routine TDM of these four drugs and is of great clinic value for individual therapy.
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Fan, Tingting, Chunhui Chen, Han Guo, Juan Xu, Jian Zhang, Xi Zhu, Yang Yang, Zhou Zhou, Lian Li, and Yuan Huang. "Design and evaluation of solid lipid nanoparticles modified with peptide ligand for oral delivery of protein drugs." European Journal of Pharmaceutics and Biopharmaceutics 88, no. 2 (October 2014): 518–28. http://dx.doi.org/10.1016/j.ejpb.2014.06.011.
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Sumi, Chandra Datta, Byung Wook Yang, In-Cheol Yeo, and Young Tae Hahm. "Antimicrobial peptides of the genus Bacillus: a new era for antibiotics." Canadian Journal of Microbiology 61, no. 2 (February 2015): 93–103. http://dx.doi.org/10.1139/cjm-2014-0613.
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The rapid onset of resistance reduces the efficacy of most conventional antimicrobial drugs and is a general cause of concern for human well-being. Thus, there is great demand for a continuous supply of novel antibiotics to combat this problem. Bacteria-derived antimicrobial peptides (AMPs) have long been used as food preservatives; moreover, prior to the development of conventional antibiotics, these AMPs served as an efficient source of antibiotics. Recently, peptides produced by members of the genus Bacillus were shown to have a broad spectrum of antimicrobial activity against pathogenic microbes. Bacillus-derived AMPs can be synthesized both ribosomally and nonribosomally and can be classified according to peptide biosynthesis, structure, and molecular weight. The precise mechanism of action of these AMPs is not yet clear; however, one proposed mechanism is that these AMPs kill bacteria by forming channels in and (or) disrupting the bacterial cell wall. Bacillus-derived AMPs have potential in the pharmaceutical industry, as well as the food and agricultural sectors. Here, we focus on Bacillus-derived AMPs as a novel alternative approach to antibacterial drug development. We also provide an overview of the biosynthesis, mechanisms of action, applications, and effectiveness of different AMPs produced by members of the Bacillus genus, including several recently identified novel AMPs.
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IRWIN, W. J. "Stability and Characterization of Protein and Peptide Drugs. Case Histories (Pharmaceutical Biotechnology Volume 5) Edited by Y. John Wang and Rodney Pearlman." Journal of Pharmacy and Pharmacology 47, no. 2 (February 1995): 176. http://dx.doi.org/10.1111/j.2042-7158.1995.tb05773.x.
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Nava, Gerardo M., Magdalena Escorcia, and M. Pilar Castañeda. "Molecular Diversity of the Antimicrobial Domain of Beta-Defensin 3 and Homologous Peptides." Comparative and Functional Genomics 2009 (2009): 1–8. http://dx.doi.org/10.1155/2009/983636.
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Human -defensin 3 has received great interest for possible pharmaceutical applications. To characterize the biology of this antimicrobial peptide, the mouse -defensin 14 has been selected as a prototypical model. This report provides definite evidence of true orthology between these defensins and reveals molecular diversity of a mammalian specific domain responsible for their antimicrobial activity. Specifically, this analysis demonstrates that eleven amino acid residues of the antimicrobial domain have been mutated by positive selection to confer protein niche specialization. These data support the notion that natural selection acts as evolutionary force driving the proliferation and diversification of defensins and introduce a novel strategy for the design of more effective antibiotics.
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Fernández Balaguer, Gonzalo, Carmen del Águila, Carolina Hurtado Marcos, and Rubén Agudo Torres. "ANCESTRAL RECONSTRUCTION OF A β-LACTAMASE AND COMPARISON WITH ITS EXTANT PROTEINS." Anales de la Real Academia Nacional de Farmacia, no. 87(02) (2021): 155–70. http://dx.doi.org/10.53519/analesranf.2021.87.02.05.
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The β-lactamases are proteins of bacterial origin that are characterized by hydrolyzing antibiotics β-lactams, conferring microbial resistance against them. They are a heterogeneous family of proteins very relevant from a health point of view due to the ease they present to acquire resistance to new drugs due to their high capacity for evolution. The in vitro evolution of these proteins has served not only to develop their characterization and improve their knowledge, but as a new line of research that allows to predictively identify residues involved in the acquisition of antibiotic resistance. At the same time, the method of ancestral protein reconstruction has been revealed as a novel and useful tool to understand the evolution of β-lactamases and understand some of their characteristics such as their promiscuity. In this work, a study of ancestral β-lactamases reconstructed from the phylogeny of existing class A β-lactamases has been carried out. Of the four ancestral proteins studied, one has been obtained that is functional and has compared its hydrolytic activity with that of four of its current counterparts against eight β-lactam drugs. This ancestral protein has been shown to have a more generalistic antibiotic activity than any of the current proteins studied. In addition, the active ancestral protein showed more resistance to one of the drugs used than the rest of β-lactamases existing. Finally these results have been discussed and from them it is argued why reconstructed ancestral sequences can be a very attractive starting point when it comes to direct evolution of proteins for obtaining proteins of biotechnological interest.
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Narang, Deepak, Jeevan Singh Tityal, Amit Jain, Reena Kulshreshtra, and Fatima Khan. "Nanobiotics: Challenging the anti-microbial perspective - The game changer?" International Journal of Bioassays 6, no. 10 (October 1, 2017): 5518. http://dx.doi.org/10.21746/ijbio.2017.6.10.2.
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Antibiotics are the most important medical inventions in human history and are the invaluable weapons to fight against various infectious diseases. Multi drug resistant microorganisms are becoming a serious issue and increasingly public health problem in present day scenario. Antibiotics are becoming less useful due to increasing bacterial resistance. Development of new and more powerful antibiotics leading to drastic pathogens response by developing resistance to the point where the most powerful drugs in our arsenal are no longer effective against them. New strategies for the management of bacterial diseases are urgently needed and nanomaterials can be a very promising approach. Nanobiotics uses nano-sized tools for the successful management bacterial diseases and to gain increased understanding of the complex underlying patho-physiology of disease. (European Science Foundation. Forward Look Nanomedicine: An EMRC Consensus Opinion 2005. Available online: http://www.esf.org (accessed on 15 July 2017). The application of nanotechnologies to medicine, or nanomedicine, which has already demonstrated its tremendous impact on the pharmaceutical and biotechnology industries, is rapidly becoming a major driving force behind ongoing changes in the antimicrobial field. Present review providing important insights on nanobiotics, and their preparation, mechanism of action, as well as perspectives on the opportunities and challenges in nanobiotics.
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Fukushima, Keizo, Ayaka Ise, Hiromi Morita, Ryo Hasegawa, Yukako Ito, Nobuyuki Sugioka, and Kanji Takada. "Two-Layered Dissolving Microneedles for Percutaneous Delivery of Peptide/Protein Drugs in Rats." Pharmaceutical Research 28, no. 1 (March 19, 2010): 7–21. http://dx.doi.org/10.1007/s11095-010-0097-7.
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Haughey, Simon A., and G. Andrew Baxter. "Biosensor Screening for Veterinary Drug Residues in Foodstuffs." Journal of AOAC INTERNATIONAL 89, no. 3 (May 1, 2006): 862–67. http://dx.doi.org/10.1093/jaoac/89.3.862.
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Abstract The advent of the surface plasmon resonance (SPR) biosensor has led to many applications in diverse fields from the pharmaceutical industry to the life sciences and other areas within biotechnology. One area that has seen a significant increase in applications is the testing for veterinary drug residues in foodstuffs. These include tests for antibiotics, β-agonists, and antiparasitic drugs. The introduction of the Biacorer<sup/>Q in the late 1990s, an SPR biosensor dedicated to the food industry, and the complementary development of kits to test for these residues mean that end users have a viable alternative screening test to the established enzyme-linked immunosorbent assay (ELISA) techniques. This paper reviews many SPR biosensor veterinary drug tests that have been developed, with particular emphasis placed on kit-based assays.
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Gupta, Divya, Mukesh Kumar, and Vishal Gupta. "AN IN VITRO INVESTIGATION OF ANTIMICROBIAL EFFICACY OF EUPHORBIA HIRTA AND MURRAYA KOENIGII AGAINST SELECTED PATHOGENIC MICROORGANISMS." Asian Journal of Pharmaceutical and Clinical Research 11, no. 5 (May 1, 2018): 359. http://dx.doi.org/10.22159/ajpcr.2018.v11i5.24578.
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Objective: To investigate the solvent-dependent antimicrobial activity and phytochemical analysis of extracts of Euphorbia hirta (leaves and flowers) and Murraya koenigii (leaves), as well as to evaluate the synergistic activity of these medicinal extracts with suitable antibiotic discs and antibiotics susceptibility of selected pathogenic microorganisms.Methods: The antimicrobial activity of the medicinal extracts was screened through agar well diffusion method and antibiotics susceptibility of selected microorganisms was investigated using disc diffusion method. A combined agar well diffusion and disc diffusion methods were used for the determination of synergistic activities of the extracts with antibiotic discs.Results: Among the different solvents, ethanol had maximum zone of inhibition against the test pathogens. Ethanolic leaf extracts of E. hirta exhibited the highest inhibitory activity against Candida albicans and Staphylococcus aureus with minimum inhibitory concentration value of 12.5 mg/mL and 25.0 mg/mL, respectively. Antimicrobial assay revealed that E. hirta extracts were active against all tested Gram-negative bacteria. However, none of the plant extracts had inhibitory activity against Gram-positive bacterium Propionibacterium acnes. Phytochemical screening for both the extracts from E. hirta revealed the presence of steroid, tannin, terpenoids, carbohydrates, alkaloid, flavonoid, diterpene, and glycoside, whereas M. koenigii extract was rich in saponins, protein, steroid, tannin, carbohydrates, alkaloid, flavonoid, and glycoside.Conclusion: The present study proposes that E. hirta and M. koenigii extracts are excellent sources of natural bioactive compounds that could be used as potent antimicrobial drugs to counter the emerging problem of antibiotic resistance of pathogenic microorganisms.
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Rybtke, Morten T., Bradley R. Borlee, Keiji Murakami, Yasuhiko Irie, Morten Hentzer, Thomas E. Nielsen, Michael Givskov, Matthew R. Parsek, and Tim Tolker-Nielsen. "Fluorescence-Based Reporter for Gauging Cyclic Di-GMP Levels in Pseudomonas aeruginosa." Applied and Environmental Microbiology 78, no. 15 (May 11, 2012): 5060–69. http://dx.doi.org/10.1128/aem.00414-12.
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ABSTRACTThe increased tolerance toward the host immune system and antibiotics displayed by biofilm-formingPseudomonas aeruginosaand other bacteria in chronic infections such as cystic fibrosis bronchopneumonia is of major concern. Targeting of biofilm formation is believed to be a key aspect in the development of novel antipathogenic drugs that can augment the effect of classic antibiotics by decreasing antimicrobial tolerance. The second messenger cyclic di-GMP is a positive regulator of biofilm formation, and cyclic di-GMP signaling is now regarded as a potential target for the development of antipathogenic compounds. Here we describe the development of fluorescent monitors that can gauge the cellular level of cyclic di-GMP inP. aeruginosa. We have created cyclic di-GMP level reporters by transcriptionally fusing the cyclic di-GMP-responsivecdrApromoter to genes encoding green fluorescent protein. We show that the reporter constructs give a fluorescent readout of the intracellular level of cyclic di-GMP inP. aeruginosastrains with different levels of cyclic di-GMP. Furthermore, we show that the reporters are able to detect increased turnover of cyclic di-GMP mediated by treatment ofP. aeruginosawith the phosphodiesterase inducer nitric oxide. Considering that biofilm formation is a necessity for the subsequent development of a chronic infection and therefore a pathogenicity trait, the reporters display a significant potential for use in the identification of novel antipathogenic compounds targeting cyclic di-GMP signaling, as well as for use in research aiming at understanding the biofilm biology ofP. aeruginosa.
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Tomono, Takumi, Haruya Yagi, Masami Ukawa, Seiya Ishizaki, Takahiro Miwa, Mao Nonomura, Ryoji Igi, et al. "Nasal absorption enhancement of protein drugs independent to their chemical properties in the presence of hyaluronic acid modified with tetraglycine-L-octaarginine." European Journal of Pharmaceutics and Biopharmaceutics 154 (September 2020): 186–94. http://dx.doi.org/10.1016/j.ejpb.2020.07.003.
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Ali, Mohammad A., Mohammad Abul Farah, Khalid M. Al-Anazi, Syed H. Basha, Fang Bai, Joongku Lee, Fahad M. A. Al-Hemaid, Ahmed H. Mahmoud, and Waleed A. Q. Hailan. "In Silico Elucidation of the Plausible Inhibitory Potential of Withaferin A of Withania Somnifera Medicinal Herb Against Breast Cancer Targeting Estrogen Receptor." Current Pharmaceutical Biotechnology 21, no. 9 (June 9, 2020): 842–51. http://dx.doi.org/10.2174/1389201021666200129121843.
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Background: Estrogen Receptors (ER) are members of the nuclear intracellular receptors family. ER once activated by estrogen, it binds to DNA via translocating into the nucleus and regulates the activity of various genes. Withaferin A (WA) - an active compound of a medicinal plant Withania somnifera was reported to be a very effective anti-cancer agent and some of the recent studies has demonstrated that WA is capable of arresting the development of breast cancer via targeting estrogen receptor. Objective: The present study is aimed at understanding the molecular level interactions of ER and Tamoxifen in comparison to Withaferin A using In-silico approaches with emphasis on Withaferin A binding capability with ER in presence of point mutations which are causing de novo drug resistance to existing drugs like Tamoxifen. Methods: Molecular modeling and docking studies were performed for the Tamoxifen and Withaferin A with the Estrogen receptor. Molecular docking simulations of estrogen receptor in complex with Tamoxifen and Withaferin A were also performed. Results: Amino acid residues, Glu353, Arg394 and Leu387 was observed as crucial for binding and stabilizing the protein-ligand complex in case of Tamoxifen and Withaferin-A. The potential of Withaferin A to overcome the drug resistance caused by the mutations in estrogen receptor to the existing drugs such as Tamoxifen was demonstrated. Conclusion: In-silico analysis has elucidated the binding mode and molecular level interactions which are expected to be of great help in further optimizing Withaferin A or design / discovery of future breast cancer inhibitors targeting estrogen receptor.
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Stark, Holger. "Von der „Blobology“ zur atomaren Auflösung der Kryo-Elektronenmikroskopie." BIOspektrum 26, no. 7 (November 2020): 710–13. http://dx.doi.org/10.1007/s12268-020-1480-5.
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AbstractIt took almost a century to develop electron microscopy into a powerful method for high-resolution structure determination of proteins. Technical improvements in microscopy, detector technology, and image processing software contributed to the exponential growth of high-resolution structures of protein complexes determined by cryo-electron microscopy in recent years. We now succeeded in breaking another resolution barrier in cryo-electron microscopy and for the first time in achieving true atomic resolution, where single atoms in the protein can indeed be visualized individually. These improvements in cryo-EM indicate that the method will continue to gain importance, not only as a method for structure determination but also in the development of new drugs in pharmaceutical research.
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Beslin, Leena Grace, and Geni G. "Biochemical Profile and Antibacterial Examination of Freshwater Crab Scylla Serrata (FORSKAL, 1775)." International Journal of Clinical Inventions and Medical Science 3, no. 2 (September 19, 2021): 53–65. http://dx.doi.org/10.36079/lamintang.ijcims-0302.233.
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Natural products from the aquatic organisms provide unlimited opportunities for the production of new drugs. To verify this fact in the present study ‘the biochemical profile and antimicrobial activity of different samples of the estuarine crab, Sylla serrata’ was investigated. Biochemical study of the body parts of the crab gains substantial attention for their specificity in connection to the food values of the crab and for the evaluation of their physiological needs at different periods of life. The total protein was estimated by Lowry's method and the amount of protein was highest in the soft muscle sample (20.27mg/ml). The total sugar was estimated by the Phenol-Sulphuric acid method and it was highest in the leg sample (209.8mg/ml). The lipids of the samples were estimated by Folchs method. Lipid was highest in the shell sample (28.35mg/ml). Thin Layer chromatography was done for characterization of protein. Antibiotics are used against bacterial infections. The natural products gained importance to screen antibiotics. For this reason the antibacterial activity of the samples were tested against grampositive and gramnegative pathogenic bacterial strains. The bacterial strains like Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Enterobacter aerogenes were used as the test strains. In the present study, the ethanol extract of crab sample I showed maximum zone of inhibition (13 mm) in P. aeruginosa. The sample I showed moderate zone of inhibition (11 mm) in K.pneumoniae. The sample II showed the minimum zone of inhibition (7 mm) in P. aeruginosa. It indicated that the shell of crabs would be a good source of antimicrobial agents and would replace the existing inadequate and cost effective antibiotics. The microbial associates of crustaceans have proven to be a rich source of bioactivity with antimicrobial and cytotoxic effects. So the organism used in the present study will be the promising source to the biotechnological and pharmaceutical applications.
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Gamal, Mohammed, and Lobna Mohammed Abd Elhalim. "Novel Eco-friendly HPLC Methods Using Refractive Index Detector for Analysis of Three Veterinary Antibiotics in Pharmaceutical Formulations and Rat Plasma." Journal of Chromatographic Science 58, no. 10 (September 8, 2020): 940–50. http://dx.doi.org/10.1093/chromsci/bmaa065.
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Abstract Antibiotic resistance increases the human mortality rate nowadays. The main purpose of the present study was to develop green reversed-phase high-performance liquid chromatography (RP-HPLC) methods with a refractive index detector for the assay of the three veterinary antibiotics (VAs), i.e., maduramicin ammonium (MA), apramycin sulfate (AS) and clarithromycin (CLA) in pharmaceutical dosage forms and spiked rat plasma. The method utilized isocratic elution using an ODP-40 C18 column, the flow rate was set at 1.0 mL/min and negative polar signals. The linearity ranges were 3.0–18.0 μg/mL for MA, 1.5–4.0 μg/mL for AS and 0.5 to 3.0 μg/mL for CLA, respectively. Liquid-liquid extraction (LLE) procedure was optimized in plasma samples. The recoveries percentages were 85.4, 81.2 and 88.8 correspondingly, in rat plasma. However, the drugs extraction by protein precipitation method yields very poor recoveries (around 50%). The new HPLC- refractive index (RI) methods are better than the previously reported HPLC-ultra violet methods in terms of greenness and simplicity of procedures. Moreover, the previously reported LC–MS methods lack the simplicity and availability of such expensive techniques in Quality control (QC) labs. The novelty of this research is the use of refractive index detector for the first time for VAs analysis.
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Yang, Baoyu, Jing Mao, Bing Gao, and Xiuli Lu. "Computer-Assisted Drug Virtual Screening Based on the Natural Product Databases." Current Pharmaceutical Biotechnology 20, no. 4 (May 28, 2019): 293–301. http://dx.doi.org/10.2174/1389201020666190328115411.
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Background:Computer-assisted drug virtual screening models the process of drug screening through computer simulation technology, by docking small molecules in some of the databases to a certain protein target. There are many kinds of small molecules databases available for drug screening, including natural product databases.Methods:Plants have been used as a source of medication for millennia. About 80% of drugs were either natural products or related analogues by 1990, and many natural products are biologically active and have favorable absorption, distribution, metabolization, excretion, and toxicology.Results:In this paper, we review the natural product databases’ contributions to drug discovery based on virtual screening, focusing particularly on the introductions of plant natural products, microorganism natural product, Traditional Chinese medicine databases, as well as natural product toxicity prediction databases.Conclusion:We highlight the applications of these databases in many fields of virtual screening, and attempt to forecast the importance of the natural product database in next-generation drug discovery.
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Mann, Greg, and Frédéric V. Stanger. "A Bio-logical Approach to Catalysis in the Pharmaceutical Industry." CHIMIA International Journal for Chemistry 74, no. 5 (May 27, 2020): 407–17. http://dx.doi.org/10.2533/chimia.2020.407.
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Enzymes have the potential to catalyse complex chemical reactions with unprecedented selectivity, under mild conditions in aqueous media. Accordingly, there is serious interest from the pharmaceutical industry to utilize enzymes as biocatalysts to produce medicines in an environmentally sustainable and economic manner. Prominent advances in the field of biotechnology have transformed this potential into a reality. Using modern protein engineering techniques, in a matter of months it is possible to evolve an enzyme, which fits the demands of a chemical process, or even to catalyse entirely novel chemistry. Consequently, biocatalysis is routinely applied throughout the pharmaceutical industry for a variety of applications, ranging from the manufacture of large volumes of high value blockbuster drugs to expanding the chemical space available for drug discovery.
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Yu, Rong-Guo, Jia-Yu Zhang, Zhen-Tao Liu, You-Guang Zhuo, Hai-Yang Wang, Jie Ye, Nannan Liu, and Yi-Yuan Zhang. "Text Mining-Based Drug Discovery in Osteoarthritis." Journal of Healthcare Engineering 2021 (April 14, 2021): 1–14. http://dx.doi.org/10.1155/2021/6674744.
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Background. Osteoarthritis (OA) is a chronic and degenerative joint disease, which causes stiffness, pain, and decreased function. At the early stage of OA, nonsteroidal anti-inflammatory drugs (NSAIDs) are considered the first-line treatment. However, the efficacy and utility of available drug therapies are limited. We aim to use bioinformatics to identify potential genes and drugs associated with OA. Methods. The genes related to OA and NSAIDs therapy were determined by text mining. Then, the common genes were performed for GO, KEGG pathway analysis, and protein-protein interaction (PPI) network analysis. Using the MCODE plugin-obtained hub genes, the expression levels of hub genes were verified using quantitative real-time polymerase chain reaction (qRT-PCR). The confirmed genes were queried in the Drug Gene Interaction Database to determine potential genes and drugs. Results. The qRT-PCR result showed that the expression level of 15 genes was significantly increased in OA samples. Finally, eight potential genes were targetable to a total of 53 drugs, twenty-one of which have been employed to treat OA and 32 drugs have not yet been used in OA. Conclusions. The 15 genes (including PTGS2, NLRP3, MMP9, IL1RN, CCL2, TNF, IL10, CD40, IL6, NGF, TP53, RELA, BCL2L1, VEGFA, and NOTCH1) and 32 drugs, which have not been used in OA but approved by the FDA for other diseases, could be potential genes and drugs, respectively, to improve OA treatment. Additionally, those methods provided tremendous opportunities to facilitate drug repositioning efforts and study novel target pharmacology in the pharmaceutical industry.
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Castiglia, Daniela, Simone Landi, and Sergio Esposito. "Advanced Applications for Protein and Compounds from Microalgae." Plants 10, no. 8 (August 16, 2021): 1686. http://dx.doi.org/10.3390/plants10081686.
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Algal species still show unrevealed and unexplored potentiality for the identification of new compounds. Photosynthetic organisms represent a valuable resource to exploit and sustain the urgent need of sustainable and green technologies. Particularly, unconventional organisms from extreme environments could hide properties to be employed in a wide range of biotechnology applications, due to their peculiar alleles, proteins, and molecules. In this review we report a detailed dissection about the latest and advanced applications of protein derived from algae. Furthermore, the innovative use of modified algae as bio-reactors to generate proteins or bioactive compounds was discussed. The latest progress about pharmaceutical applications, including the possibility to obtain drugs to counteract virus (as SARS-CoV-2) were also examined. The last paragraph will survey recent cases of the utilization of extremophiles as bio-factories for specific protein and molecule production.
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Nadanaciva, Sashi, Keith Dillman, David F. Gebhard, Alka Shrikhande, and Yvonne Will. "High-Content Screening for Compounds That Affect mtDNA-Encoded Protein Levels in Eukaryotic Cells." Journal of Biomolecular Screening 15, no. 8 (July 12, 2010): 937–48. http://dx.doi.org/10.1177/1087057110373547.
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Compounds that interfere with the synthesis of either mitochondrial DNA or mtDNA-encoded proteins reduce the levels of 13 proteins essential for oxidative phosphorylation, leading to a decrease in mitochondrial adenosine triphosphate (ATP) production. Toxicity caused by these compounds is seldom identified in 24- to 72-h cytotoxicity assays due to the low turnover rates of both mtDNA and mtDNA-encoded proteins. To address this problem, the authors developed a 96-well format, high-content screening (HCS) assay that measures, in eukaryotic cells, the level of Complex IV–subunit 1, an mtDNA-encoded protein synthesized on mitochondrial ribosomes, and the level of Complex V–α subunit, a nuclear DNA-encoded protein synthesized on cytosolic ribosomes. The effect of several antibiotics and antiretrovirals on these 2 proteins was assessed, in transformed human liver epithelial cells, 6 days after compound treatment. The results confirmed effects of drugs known to reduce mtDNA-encoded protein levels and also revealed novel information showing that several fluoroquinolones and a macrolide, josamycin, impaired expression of mtDNA-encoded proteins. The HCS assay was robust with an average Z′ factor of 0.62. The assay enables large-scale screening of compounds to identify those that potentially affect mtDNA-encoded protein levels and can be implemented within a screening paradigm to minimize compound attrition.
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ROSS, Heike, Christopher G. ARMSTRONG, and Philip COHEN. "A non-radioactive method for the assay of many serine/threonine-specific protein kinases." Biochemical Journal 366, no. 3 (September 15, 2002): 977–81. http://dx.doi.org/10.1042/bj20020786.
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The generation of drugs that modulate the activities of particular protein kinases has become a prime focus of the pharmaceutical and biotechnology industry. Consequently, improved methods for the development of high-throughput screening formats for these enzymes is a high priority. In the present study, we have designed three generic peptide substrates that can be used to assay a diverse range of protein kinases. These peptides share a common seven-residue epitope that includes the site of phosphorylation, and against which we have generated a phospho-specific antibody. Thus a large number of serine/threonine-specific protein kinases can be screened using a simple non-radioactive format.
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Hou, Huiwen, Juan Wang, Jie Wang, Wen Tang, Abdul Sami Shaikh, Yan Li, Jiaai Fu, et al. "A Review of Bioactive Peptides: Chemical Modification, Structural Characterization and Therapeutic Applications." Journal of Biomedical Nanotechnology 16, no. 12 (December 1, 2020): 1687–718. http://dx.doi.org/10.1166/jbn.2020.3001.
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In recent years, the development and applications of protein drugs have attracted extensive attention from researchers. However, the shortcomings of protein drugs also limit their further development. Therefore, bioactive peptides isolated or simulated from protein polymers have broad application prospects in food, medicine, biotechnology, and other industries. Such peptides have a molecular weight distribution between 180 and 1000 Da. As a small molecule substance, bioactive peptide is usually degraded by various enzymes in the organism and have a short half-life. At the same time, such substances have poor stability and are difficult to produce and store. Therefore, these active peptides may be modified through phosphorylation, glycosylation, and acylation. Compared with other protein drugs, the modified active peptides are more easily absorbed by the body, have longer half-life, stronger targeting, and fewer side effects in addition to higher bioavailability. In the light of their functions, bioactive peptide can be divided into antimicrobial, anti-tumour, anti-angiogenic, antioxidant, anti-fatigue, and anti-hypertensive peptides. This article mainly focuses on the introduction of several promising biologically active peptides functioning as antimicrobial, anti-tumour, antiangiogenic, and antioxidant peptides from the three aspects modification, structural characteristics and mechanism of action.
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Li, Mingyang, Wei Shi, Jia Yang, Qi Wang, Haiyan Dong, Jun Chen, Lifang Zhang, and Shanli Zhu. "Generation of a novel affibody molecule targeting Chlamydia trachomatis MOMP." Applied Microbiology and Biotechnology 105, no. 4 (February 2021): 1477–87. http://dx.doi.org/10.1007/s00253-021-11128-x.
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Abstract Chlamydia trachomatis (C. trachomatis) is the leading cause of preventable blindness worldwide and the most prevalent cause of bacterial sexually transmitted diseases. At present, there is no available vaccine, and recurrences after antibiotics treatment are substantial problems. Major outer membrane protein (MOMP) accounts for 60% of the outer mass of C. trachomatis, functioning as trimeric porin, and it is highly antigenic. Therefore, MOMP is the most promising candidate for vaccine developing and target therapy of Chlamydia. Affibody, a new class of affinity ligands derived from the Z-domain in the binding region of Staphylococcus aureus protein A, has been the focus of researchers as a viable alternative to antibodies. In this study, the MOMP-targeted affibody molecule (ZMOMP:461) was screened by phage-displayed peptide library. Further, the affinity and specificity were characterized by surface plasmon resonance (SPR) and Western blot. Immunofluorescence assay (IFA) indicated that the MOMP-binding affibody could recognize native MOMP in HeLa229 cells infected C. trachomatis. Immunoprecipitation assay confirmed further that ZMOMP:461 molecule specifically recognizes the epitope on relaxed trimer MOMP. Our findings provide strong evidence that affibody molecule (ZMOMP:461) serves as substitute for MOMP antibody for biological applications and has a great potential for delivering drugs for target therapy. Key points • We screened a novel affibody molecule ZMOMP:461 targeting Chlamydia trachomatis MOMP. • ZMOMP:461 recognizes the recombinant and native MOMP with high affinity and specificity. • ZMOMP:461 could be internalized into live target cells.
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Pontes, Jorge F., and Ana Grenha. "Multifunctional Nanocarriers for Lung Drug Delivery." Nanomaterials 10, no. 2 (January 21, 2020): 183. http://dx.doi.org/10.3390/nano10020183.
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Nanocarriers have been increasingly proposed for lung drug delivery applications. The strategy of combining the intrinsic and more general advantages of the nanostructures with specificities that improve the therapeutic outcomes of particular clinical situations is frequent. These include the surface engineering of the carriers by means of altering the material structure (i.e., chemical modifications), the addition of specific ligands so that predefined targets are reached, or even the tuning of the carrier properties to respond to specific stimuli. The devised strategies are mainly directed at three distinct areas of lung drug delivery, encompassing the delivery of proteins and protein-based materials, either for local or systemic application, the delivery of antibiotics, and the delivery of anticancer drugs—the latter two comprising local delivery approaches. This review addresses the applications of nanocarriers aimed at lung drug delivery of active biological and pharmaceutical ingredients, focusing with particular interest on nanocarriers that exhibit multifunctional properties. A final section addresses the expectations regarding the future use of nanocarriers in the area.
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Crowther, Gregory J., S. Arshiya Quadri, Benjamin J. Shannon-Alferes, Wesley C. Van Voorhis, and Henry Rosen. "A Mechanism-Based Whole-Cell Screening Assay to Identify Inhibitors of Protein Export in Escherichia coli by the Sec Pathway." Journal of Biomolecular Screening 17, no. 4 (January 10, 2012): 535–41. http://dx.doi.org/10.1177/1087057111431606.
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More than 20% of bacterial proteins are noncytoplasmic, and most of these pass through the SecYEG channel en route to the periplasm, cell membrane, or surrounding environment. The Sec pathway, encompassing SecYEG and several associated proteins (SecA, SecB, YidC, SecDFYajC), is of interest as a potential drug target because it is distinct from targets of current drugs, is essential for bacterial growth, and exhibits dissimilarities in eukaryotes and bacteria that increase the likelihood of selectively inhibiting the microbial pathway. As a step toward validating the pathway as a drug target, we have adapted a mechanism-based whole-cell assay in a manner suitable for high-throughput screening (HTS). The assay uses an engineered strain of Escherichia coli that accumulates beta-galactosidase (β-gal) in its cytoplasm if translocation through SecYEG is blocked. The assay should facilitate rapid identification of compounds that specifically block the Sec pathway because widely, toxic compounds and nonspecific protein synthesis inhibitors prevent β-gal production and thus do not register as hits. Testing of current antibiotics confirmed that they do not generally act through the Sec pathway. A mini-screen of 800 compounds indicated the assay’s readiness for larger screening projects.
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Ibrahim, Mahmoud A. A., Alaa H. M. Abdelrahman, Mohamed A. M. Atia, Tarik A. Mohamed, Mahmoud F. Moustafa, Abdulrahim R. Hakami, Shaden A. M. Khalifa, et al. "Blue Biotechnology: Computational Screening of Sarcophyton Cembranoid Diterpenes for SARS-CoV-2 Main Protease Inhibition." Marine Drugs 19, no. 7 (July 13, 2021): 391. http://dx.doi.org/10.3390/md19070391.
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The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < −33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of −43.8 and −34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.
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Lykoshin, D. D., V. V. Zaitsev, M. A. Kostromina, and R. S. Esipov. "New-generation osteoplastic materials based on biological and synthetic matrices." Fine Chemical Technologies 16, no. 1 (March 18, 2021): 36–54. http://dx.doi.org/10.32362/2410-6593-2021-16-1-36-54.
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Objectives. The purpose of this analytical review is to evaluate the market for osteoplastic materials and surgical implants, as well as study the features of new-generation materials and the results of clinical applications.Methods. This review summarizes the volumes of research articles presented in the electronic database PubMed and eLIBRARY. A total of 129 scientific articles related to biological systems, calcium phosphate, polymer, and biocomposite matrices as carriers of pharmaceutical substances, primary recombinant protein osteoinductors, antibiotics, and biologically active chemical reagents were analyzed and summarized. The search depth was 10 years.Results. Demineralized bone matrix constitutes 26% of all types of osteoplastic matrices used globally in surgical osteology, which includes neurosurgery, traumatology and orthopedics, dentistry, and maxillofacial and pediatric surgery. Among the matrices, polymer and biocomposite matrices are outstanding. Special attention is paid to the possibility of immobilizing osteogenic factors and target pharmaceutical substances on the scaffold material to achieve controlled and prolonged release at the site of surgical implantation. Polymeric and biocomposite materials can retard the release of pharmaceutical substances at the implantation site, promoting a decrease in the toxicity and an improvement in the therapeutic effect. The use of composite scaffolds of different compositions in vivo results in high osteogenesis, promotes the initialization of biomineralization, and enables the tuning of the degradation rate of the material.Conclusions. Osteoplastic materials of various compositions in combination with drugs showed accelerated regeneration and mineralization of bone tissue in vivo, excluding systemic side reactions. Furthermore, although some materials have already been registered as commercial drugs, a plethora of unresolved problems remain. Due to the limited clinical studies of materials for use on humans, there is still an insufficient understanding of the toxicity of materials, time of their resorption, speed of drug delivery, and the possible long-term adverse effects of using implants of different compositions.
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Orlova, N. A., S. V. Kovnir, I. I. Vorobiev, A. G. Gabibov, and A. I. Vorobiev. "Blood Clotting Factor VIII: From Evolution to Therapy." Acta Naturae 5, no. 2 (June 15, 2013): 19–39. http://dx.doi.org/10.32607/20758251-2013-5-2-19-39.
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Recombinant blood clotting factor VIII is one of the most complex proteins for industrial manufacturing due to the low efficiency of its gene transcription, massive intracellular loss of its proprotein during post-translational processing, and the instability of the secreted protein. Improvement in hemophilia A therapy requires a steady increase in the production of factor VIII drugs despite tightening standards of product quality and viral safety. More efficient systems for heterologous expression of factor VIII can be created on the basis of the discovered properties of its gene transcription, post-translational processing, and behavior in the bloodstream. The present review describes the deletion variants of factor VIII protein with increased secretion efficiency and the prospects for the pharmaceutical development of longer acting variants and derivatives of factor VIII.
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Burrin, Douglas, Per Torp Sangild, Barbara Stoll, Thomas Thymann, Randal Buddington, Juan Marini, Oluyinka Olutoye, and Robert J. Shulman. "Translational Advances in Pediatric Nutrition and Gastroenterology: New Insights from Pig Models." Annual Review of Animal Biosciences 8, no. 1 (February 15, 2020): 321–54. http://dx.doi.org/10.1146/annurev-animal-020518-115142.
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Pigs are increasingly important animals for modeling human pediatric nutrition and gastroenterology and complementing mechanistic studies in rodents. The comparative advantages in size and physiology of the neonatal pig have led to new translational and clinically relevant models of important diseases of the gastrointestinal tract and liver in premature infants. Studies in pigs have established the essential roles of prematurity, microbial colonization, and enteral nutrition in the pathogenesis of necrotizing enterocolitis. Studies in neonatal pigs have demonstrated the intestinal trophic effects of akey gut hormone, glucagon-like peptide 2 (GLP-2), and its role in the intestinal adaptation process and efficacy in the treatment of short bowel syndrome. Further, pigs have been instrumental in elucidating the physiology of parenteral nutrition–associated liver disease and the means by which phytosterols, fibroblast growth factor 19, and a new generation of lipid emulsions may modify disease. The premature pig will continue to be a valuable model in the development of optimal infant diets (donor human milk, colostrum), specific milk bioactives (arginine, growth factors), gut microbiota modifiers (pre-, pro-, and antibiotics), pharmaceutical drugs (GLP-2 analogs, FXR agonists), and novel diagnostic tools (near-infrared spectroscopy) to prevent and treat these pediatric diseases.
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Miró-Canturri, Andrea, Rafael Ayerbe-Algaba, Raquel del Toro, Manuel Enrique-Jiménez Mejías, Jerónimo Pachón, and Younes Smani. "Potential Tamoxifen Repurposing to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli." Pharmaceuticals 14, no. 6 (May 26, 2021): 507. http://dx.doi.org/10.3390/ph14060507.
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The development of new strategic therapies for multidrug-resistant bacteria, like the use of non-antimicrobial approaches and/or drugs repurposed to be used as monotherapies or in combination with clinically relevant antibiotics, has become urgent. A therapeutic alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune system modulation to improve the infection clearance. We showed that immunocompetent mice pretreated with tamoxifen at 80 mg/kg/d for three days and infected with Acinetobacter baumannii, Pseudomonas aeruginosa, or Escherichia coli in peritoneal sepsis models showed reduced release of the monocyte chemotactic protein-1 (MCP-1) and its signaling pathway interleukin-18 (IL-18), and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). This reduction of MCP-1 induced the reduction of migration of inflammatory monocytes and neutrophils from the bone marrow to the blood. Indeed, pretreatment with tamoxifen in murine peritoneal sepsis models reduced the bacterial load in tissues and blood, and increased mice survival from 0% to 60–100%. Together, these data show that tamoxifen presents therapeutic efficacy against MDR A. baumannii, P. aeruginosa, and E. coli in experimental models of infection and may be a new candidate to be repurposed as a treatment for GNB infections.
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Kell, Douglas B. "The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes." Molecules 26, no. 18 (September 16, 2021): 5629. http://dx.doi.org/10.3390/molecules26185629.
Full textAbstract:
Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real biomembranes are mostly protein, not lipid, (ii) unlike purely lipid bilayers that can form transient aqueous channels, the high concentrations of proteins serve to stop such activity, (iii) natural evolution long ago selected against transport methods that just let any undesirable products enter a cell, (iv) transporters have now been identified for all kinds of molecules (even water) that were once thought not to require them, (v) many experiments show a massive variation in the uptake of drugs between different cells, tissues, and organisms, that cannot be explained if lipid bilayer transport is significant or if efflux were the only differentiator, and (vi) many experiments that manipulate the expression level of individual transporters as an independent variable demonstrate their role in drug and nutrient uptake (including in cytotoxicity or adverse drug reactions). This makes such transporters valuable both as a means of targeting drugs (not least anti-infectives) to selected cells or tissues and also as drug targets. The same considerations apply to the exploitation of substrate uptake and product efflux transporters in biotechnology. We are also beginning to recognise that transporters are more promiscuous, and antiporter activity is much more widespread, than had been realised, and that such processes are adaptive (i.e., were selected by natural evolution). The purpose of the present review is to summarise the above, and to rehearse and update readers on recent developments. These developments lead us to retain and indeed to strengthen our contention that for transmembrane pharmaceutical drug transport “phospholipid bilayer transport is negligible”.
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Hu, Haifeng, and Kozo Ochi. "Novel Approach for Improving the Productivity of Antibiotic-Producing Strains by Inducing Combined Resistant Mutations." Applied and Environmental Microbiology 67, no. 4 (April 1, 2001): 1885–92. http://dx.doi.org/10.1128/aem.67.4.1885-1892.2001.
Full textAbstract:
ABSTRACT We developed a novel approach for improving the production of antibiotic from Streptomyces coelicolor A3(2) by inducing combined drug-resistant mutations. Mutants with enhanced (1.6- to 3-fold-higher) actinorhodin production were detected at a high frequency (5 to 10%) among isolates resistant to streptomycin (Strr), gentamicin (Genr), or rifampin (Rifr), which developed spontaneously on agar plates which contained one of the three drugs. Construction of double mutants (str gen and str rif) by introducing gentamicin or rifampin resistance into anstr mutant resulted in further increased (1.7- to 2.5-fold-higher) actinorhodin productivity. Likewise, triple mutants (str gen rif) thus constructed were found to have an even greater ability for producing the antibiotic, eventually generating a mutant able to produce 48 times more actinorhodin than the wild-type strain. Analysis ofstr mutants revealed that a point mutation occurred within the rpsL gene, which encodes the ribosomal protein S12. rif mutants were found to have a point mutation in the rpoB gene, which encodes the β-subunit of RNA polymerase. Mutation points ingen mutants still remain unknown. These single, double, and triple mutants displayed in hierarchical order a remarkable increase in the production of ActII-ORF4, a pathway-specific regulatory protein, as determined by Western blotting analysis. This reflects the same hierarchical order observed for the increase in actinorhodin production. The superior ability of the triple mutants was demonstrated by physiological analyses under various cultural conditions. We conclude that by inducing combined drug-resistant mutations we can continuously increase the production of antibiotic in a stepwise manner. This new breeding approach could be especially effective for initially improving the production of antibiotics from wild-type strains.
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Veiga-Matos, Jéssica, Fernando Remião, and Ana Motales. "Pharmacokinetics and Toxicokinetics Roles of Membrane Transporters at Kidney Level." Journal of Pharmacy & Pharmaceutical Sciences 23 (September 29, 2020): 333–56. http://dx.doi.org/10.18433/jpps30865.
Full textAbstract:
Transporters are large membrane proteins, which control the passage of various compounds through biological membranes. These proteins are divided into uptake and efflux transporters and play an important role in the toxicokinetics of many endobiotics and xenobiotics. The uptake transporters facilitate the absorption of these compounds from the blood into the proximal tubular cells, while the efflux transporters eliminate these compounds into tubular fluid (urine). Overall, the uptake is performed by the superfamily solute carrier (SLC) transporters, which are, mostly, located in the basolateral membrane. The organic anion transporters (OATs; SLC22), the organic cation transporters (OCTs; SLC22), the organic cation/carnitine transporters (OCTNs), and the organic anion transporting polypeptides (OATP; SLC21/SLCO) are some examples of uptake transporters of the SLC superfamily. On the other hand, the superfamily ATP-binding cassette (ABC) transporters carry out the elimination of the substances through the apical membrane of the proximal tubular cells. The multidrug resistance proteins 1 (MDR; ABCB), the multi resistance protein (MRP2; ABCC) and the breast cancer resistance protein (BCRP, ABCG) along with the multidrug and toxin extrusion (MATE), which is an SLC transporter, carry out the substance efflux of the cell, However, uptake transporters seem to be more efficient than efflux transporters, leading to an accumulation of compounds in proximal tubular cells and, consequently, to renal damage. The accumulation of compounds can also occur due to variations in the number of transporters that exist due to differences in sex, age, genetic polymorphisms and epigenetics. Furthermore, some substances can inhibit, induce or, eventually, activate these transporters, with consequent drug-drug interactions (DDIs) as a result of alterations on the toxicokinetics of xenobiotics, leading to an increase of their accumulation and, consequently, to renal damage. These compounds may be exogenous, such as antibiotics, antivirals, cisplatin, metals, herbicides, mycotoxins and drugs; or endogenous, like uric acid, bile acids, bilirubin conjugates and conjugated steroids. Thus, in this review, we will focus on the accumulation of exogenous compounds due to variations on renal transporters and the consequent biological effects caused by them.