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      Identification of novel drug targets in bovine respiratory disease: an essential step in applying biotechnologic techniques to develop more effective therapeutic treatments

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          Abstract

          Background

          Bovine Respiratory Disease (BRD) is a major problem in cattle production which causes substantial economic loss. BRD has multifactorial aetiologies, is multi-microbial, and several of the causative pathogens are unknown. Consequently, primary management practices such as metaphylactic antimicrobial injections for BRD prevention are used to reduce the incidence of BRD in feedlot cattle. However, this poses a serious threat in the form of development of antimicrobial resistance and demands an urgent need to find novel interventions that could reduce the effects of BRD drastically and also delay/prevent bacterial resistance.

          Materials and methods

          We have employed a subtractive genomics approach that helps delineate essential, host-specific, and druggable targets in pathogens responsible for BRD. We also proposed antimicrobials from FDA green and orange book that could be repositioned for BRD.

          Results

          We have identified 107 putative targets that are essential, selective and druggable. We have also confirmed the susceptibility of two BRD pathogens to one of the proposed antimicrobials – oxytetracycline.

          Conclusion

          This approach allows for repositioning drugs known for other infections to BRD, predicting novel druggable targets for BRD infection, and providing a new direction in developing more effective therapeutic treatments for BRD.

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          Most cited references 61

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          Essential genes of a minimal bacterium.

          Mycoplasma genitalium has the smallest genome of any organism that can be grown in pure culture. It has a minimal metabolism and little genomic redundancy. Consequently, its genome is expected to be a close approximation to the minimal set of genes needed to sustain bacterial life. Using global transposon mutagenesis, we isolated and characterized gene disruption mutants for 100 different nonessential protein-coding genes. None of the 43 RNA-coding genes were disrupted. Herein, we identify 382 of the 482 M. genitalium protein-coding genes as essential, plus five sets of disrupted genes that encode proteins with potentially redundant essential functions, such as phosphate transport. Genes encoding proteins of unknown function constitute 28% of the essential protein-coding genes set. Disruption of some genes accelerated M. genitalium growth.
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            DEG 10, an update of the database of essential genes that includes both protein-coding genes and noncoding genomic elements

             Hao Luo,  Yan Lin,  Feng Gao (2013)
            The combination of high-density transposon-mediated mutagenesis and high-throughput sequencing has led to significant advancements in research on essential genes, resulting in a dramatic increase in the number of identified prokaryotic essential genes under diverse conditions and a revised essential-gene concept that includes all essential genomic elements, rather than focusing on protein-coding genes only. DEG 10, a new release of the Database of Essential Genes (available at http://www.essentialgene.org), has been developed to accommodate these quantitative and qualitative advancements. In addition to increasing the number of bacterial and archaeal essential genes determined by genome-wide gene essentiality screens, DEG 10 also harbors essential noncoding RNAs, promoters, regulatory sequences and replication origins. These essential genomic elements are determined not only in vitro, but also in vivo, under diverse conditions including those for survival, pathogenesis and antibiotic resistance. We have developed customizable BLAST tools that allow users to perform species- and experiment-specific BLAST searches for a single gene, a list of genes, annotated or unannotated genomes. Therefore, DEG 10 includes essential genomic elements under different conditions in three domains of life, with customizable BLAST tools.
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              Analyzing biological network parameters with CentiScaPe

              Summary: The increasing availability of large network datasets along with the progresses in experimental high-throughput technologies have prompted the need for tools allowing easy integration of experimental data with data derived form network computational analysis. In order to enrich experimental data with network topological parameters, we have developed the Cytoscape plug-in CentiScaPe. The plug-in computes several network centrality parameters and allows the user to analyze existing relationships between experimental data provided by the users and node centrality values computed by the plug-in. CentiScaPe allows identifying network nodes that are relevant from both experimental and topological viewpoints. CentiScaPe also provides a Boolean logic-based tool that allows easy characterization of nodes whose topological relevance depends on more than one centrality. Finally, different graphic outputs and the included description of biological significance for each computed centrality facilitate the analysis by the end users not expert in graph theory, thus allowing easy node categorization and experimental prioritization. Availability: CentiScaPe can be downloaded via the Cytoscape web site: http://chianti.ucsd.edu/cyto_web/plugins/index.php. Tutorial, centrality descriptions and example data are available at: http://profs.sci.univr.it/∼scardoni/centiscape/centiscapepage.php Contact: giovanni.scardoni@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                07 May 2018
                : 12
                : 1135-1146
                Affiliations
                [1 ]College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
                [2 ]Department of Chemistry, University of Delhi, Delhi, India
                [3 ]Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
                Author notes
                Correspondence: Meena Kishore Sakharkar; Jian Yang, College of Pharmacy and Nutrition, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada, Email meena.sakharkar@ 123456usask.ca ; jian.yang@ 123456usask.ca
                Article
                dddt-12-1135
                10.2147/DDDT.S163476
                5944452
                © 2018 Sakharkar et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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