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      Prospects of In vivo Incorporation of Non-canonical Amino Acids for the Chemical Diversification of Antimicrobial Peptides

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          Abstract

          The incorporation of non-canonical amino acids (ncAA) is an elegant way for the chemical diversification of recombinantly produced antimicrobial peptides (AMPs). Residue- and site-specific installation methods in several bacterial production hosts hold great promise for the generation of new-to-nature AMPs, and can contribute to tackle the ongoing emergence of antibiotic resistance in pathogens. Especially from a pharmacological point of view, desirable improvements span pH and protease resistance, solubility, oral availability and circulation half-life. Although the primary focus of this report is on ribosomally synthesized and post-translationally modified peptides (RiPPs), we have included selected cases of peptides produced by solid phase peptide synthesis to comparatively show the potential and impact of ncAA introduction. Generally speaking, the introduction of ncAAs in recombinant AMPs delivers novel levels of chemical diversification. Cotranslationally incorporated, they can take part in AMP biogenesis either through direction interaction with elements of the post-translational modification (PTM) machinery or as untargeted sites with unique physicochemical properties and chemical handles for further modification. Together with genetic libraries, genome mining and processing by PTM machineries, ncAAs present not a mere addition to this process, but a highly diverse pool of building blocks to significantly broaden the chemical space of this valuable class of molecules. This perspective summarizes new developments of ncAA containing peptides. Challenges to be resolved in order to reach large-scale pharmaceutical production of these promising compounds and prospects for future developments are discussed.

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          BAGEL3: automated identification of genes encoding bacteriocins and (non-)bactericidal posttranslationally modified peptides

          Identifying genes encoding bacteriocins and ribosomally synthesized and posttranslationally modified peptides (RiPPs) can be a challenging task. Especially those peptides that do not have strong homology to previously identified peptides can easily be overlooked. Extensive use of BAGEL2 and user feedback has led us to develop BAGEL3. BAGEL3 features genome mining of prokaryotes, which is largely independent of open reading frame (ORF) predictions and has been extended to cover more (novel) classes of posttranslationally modified peptides. BAGEL3 uses an identification approach that combines direct mining for the gene and indirect mining via context genes. Especially for heavily modified peptides like lanthipeptides, sactipeptides, glycocins and others, this genetic context harbors valuable information that is used for mining purposes. The bacteriocin and context protein databases have been updated and it is now easy for users to submit novel bacteriocins or RiPPs. The output has been simplified to allow user-friendly analysis of the results, in particular for large (meta-genomic) datasets. The genetic context of identified candidate genes is fully annotated. As input, BAGEL3 uses FASTA DNA sequences or folders containing multiple FASTA formatted files. BAGEL3 is freely accessible at http://bagel.molgenrug.nl.
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            Antimicrobial resistance: A global emerging threat to public health systems.

            Antimicrobial resistance (AMR) became in the last two decades a global threat to public health systems in the world. Since the antibiotic era, with the discovery of the first antibiotics that provided consistent health benefits to human medicine, the misuse and abuse of antimicrobials in veterinary and human medicine have accelerated the growing worldwide phenomenon of AMR. This article presents an extensive overview of the epidemiology of AMR, with a focus on the link between food producing-animals and humans and on the legal framework and policies currently implemented at the EU level and globally. The ways of responding to the AMR challenges foresee an array of measures that include: designing more effective preventive measures at farm level to reduce the use of antimicrobials; development of novel antimicrobials; strengthening of AMR surveillance system in animal and human populations; better knowledge of the ecology of resistant bacteria and resistant genes; increased awareness of stakeholders on the prudent use of antibiotics in animal productions and clinical arena; and the public health and environmental consequences of AMR. Based on the global nature of AMR and considering that bacterial resistance does not recognize barriers and can spread to people and the environment, the article ends with specific recommendations structured around a holistic approach and targeted to different stakeholders.
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              Click chemistry in complex mixtures: bioorthogonal bioconjugation.

              The selective chemical modification of biological molecules drives a good portion of modern drug development and fundamental biological research. While a few early examples of reactions that engage amine and thiol groups on proteins helped establish the value of such processes, the development of reactions that avoid most biological molecules so as to achieve selectivity in desired bond-forming events has revolutionized the field. We provide an update on recent developments in bioorthogonal chemistry that highlights key advances in reaction rates, biocompatibility, and applications. While not exhaustive, we hope this summary allows the reader to appreciate the rich continuing development of good chemistry that operates in the biological setting.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                02 February 2017
                2017
                : 8
                : 124
                Affiliations
                [1] 1Biocatalysis Group, Department of Chemistry, Technische Universität Berlin (Berlin Institute of Technology) Berlin, Germany
                [2] 2Molecular Genetics Group, Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, Rijksuniversiteit Groningen (University of Groningen) Groningen, Netherlands
                Author notes

                Edited by: Maria Tereza Dos Santos Correia, Federal University of Pernambuco, Brazil

                Reviewed by: Osmar Nascimento Silva, Universidade Católica Dom Bosco, Brazil; César De La Fuente, Massachusetts Institute of Technology, USA; Qi Zhang, Fudan University, China

                *Correspondence: Tobias Baumann, tobias.baumann@ 123456tu-berlin.de Nediljko Budisa, nediljko.budisa@ 123456tu-berlin.de

                These authors have contributed equally to this work.

                This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2017.00124
                5288337
                28210246
                d00071ce-1253-4da5-b1ae-7a0411275395
                Copyright © 2017 Baumann, Nickling, Bartholomae, Buivydas, Kuipers and Budisa.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 12 October 2016
                : 18 January 2017
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 73, Pages: 9, Words: 0
                Funding
                Funded by: Seventh Framework Programme 10.13039/501100004963
                Award ID: 613981
                Categories
                Microbiology
                Perspective

                Microbiology & Virology
                antibacterial peptides,lantibiotics,non-canonical amino acids,orthogonal translation,aminoacyl-trna-synthetases,non-natural peptide variants,ribosomally synthesized and post-translationally modified peptides,nisin

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