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      Detecting and prioritizing biosynthetic gene clusters for bioactive compounds in bacteria and fungi

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          Abstract

          Secondary metabolites (SM) produced by fungi and bacteria have long been of exceptional interest owing to their unique biomedical ramifications. The traditional discovery of new natural products that was mainly driven by bioactivity screening has now experienced a fresh new approach in the form of genome mining. Several bioinformatics tools have been continuously developed to detect potential biosynthetic gene clusters (BGCs) that are responsible for the production of SM. Although the principles underlying the computation of these tools have been discussed, the biological background is left underrated and ambiguous. In this review, we emphasize the biological hypotheses in BGC formation driven from the observations across genomes in bacteria and fungi, and provide a comprehensive list of updated algorithms/tools exclusively for BGC detection. Our review points to a direction that the biological hypotheses should be systematically incorporated into the BGC prediction and assist the prioritization of candidate BGC.

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          antiSMASH 4.0—improvements in chemistry prediction and gene cluster boundary identification

          Abstract Many antibiotics, chemotherapeutics, crop protection agents and food preservatives originate from molecules produced by bacteria, fungi or plants. In recent years, genome mining methodologies have been widely adopted to identify and characterize the biosynthetic gene clusters encoding the production of such compounds. Since 2011, the ‘antibiotics and secondary metabolite analysis shell—antiSMASH’ has assisted researchers in efficiently performing this, both as a web server and a standalone tool. Here, we present the thoroughly updated antiSMASH version 4, which adds several novel features, including prediction of gene cluster boundaries using the ClusterFinder method or the newly integrated CASSIS algorithm, improved substrate specificity prediction for non-ribosomal peptide synthetase adenylation domains based on the new SANDPUMA algorithm, improved predictions for terpene and ribosomally synthesized and post-translationally modified peptides cluster products, reporting of sequence similarity to proteins encoded in experimentally characterized gene clusters on a per-protein basis and a domain-level alignment tool for comparative analysis of trans-AT polyketide synthase assembly line architectures. Additionally, several usability features have been updated and improved. Together, these improvements make antiSMASH up-to-date with the latest developments in natural product research and will further facilitate computational genome mining for the discovery of novel bioactive molecules.
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            Fungal secondary metabolism - from biochemistry to genomics.

            Much of natural product chemistry concerns a group of compounds known as secondary metabolites. These low-molecular-weight metabolites often have potent physiological activities. Digitalis, morphine and quinine are plant secondary metabolites, whereas penicillin, cephalosporin, ergotrate and the statins are equally well known fungal secondary metabolites. Although chemically diverse, all secondary metabolites are produced by a few common biosynthetic pathways, often in conjunction with morphological development. Recent advances in molecular biology, bioinformatics and comparative genomics have revealed that the genes encoding specific fungal secondary metabolites are clustered and often located near telomeres. In this review, we address some important questions, including which evolutionary pressures led to gene clustering, why closely related species produce different profiles of secondary metabolites, and whether fungal genomics will accelerate the discovery of new pharmacologically active natural products.
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              The antibiotic resistome: the nexus of chemical and genetic diversity.

              Over the millennia, microorganisms have evolved evasion strategies to overcome a myriad of chemical and environmental challenges, including antimicrobial drugs. Even before the first clinical use of antibiotics more than 60 years ago, resistant organisms had been isolated. Moreover, the potential problem of the widespread distribution of antibiotic resistant bacteria was recognized by scientists and healthcare specialists from the initial use of these drugs. Why is resistance inevitable and where does it come from? Understanding the molecular diversity that underlies resistance will inform our use of these drugs and guide efforts to develop new efficacious antibiotics.
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                Author and article information

                Contributors
                +886 2 27855696 , hsiaoching@gate.sinica.edu.tw
                +886 2 27871139 , paoyang@gate.sinica.edu.tw
                Journal
                Appl Microbiol Biotechnol
                Appl. Microbiol. Biotechnol
                Applied Microbiology and Biotechnology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0175-7598
                1432-0614
                12 March 2019
                12 March 2019
                2019
                : 103
                : 8
                : 3277-3287
                Affiliations
                [1 ]ISNI 0000 0001 2287 1366, GRID grid.28665.3f, Institute of Plant and Microbial Biology, Academia Sinica, ; No. 128, Section 2, Academia Rd, Nangang District, Taipei City, 11529 Taiwan
                [2 ]ISNI 0000 0001 2287 1366, GRID grid.28665.3f, Institute of Biological Chemistry, Academia Sinica, ; No. 128, Section 2, Academia Rd, Nangang District, Taipei City, 11529 Taiwan
                Author information
                http://orcid.org/0000-0002-7402-3075
                Article
                9708
                10.1007/s00253-019-09708-z
                6449301
                30859257
                6dd54e31-bf6d-4ad2-a95f-9448bd564821
                © The Author(s) 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 11 December 2018
                : 17 February 2019
                : 18 February 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: 106-2311-B-001 -035 -MY3
                Award ID: 106-2633-B-001 -001
                Award ID: 106-2113-M-001-008-MY2
                Award ID: 107-2320-B-001-025-MY3
                Award Recipient :
                Categories
                Mini-Review
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2019

                Biotechnology
                secondary metabolites,biosynthetic gene cluster,duplicate gene,self-protection,horizontal gene transfer,bioinformatics

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