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      Regulation of antibiotic biosynthesis in actinomycetes: Perspectives and challenges

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          Abstract

          Actinomycetes are the main sources of antibiotics. The onset and level of production of each antibiotic is subject to complex control by multi-level regulators. These regulators exert their functions at hierarchical levels. At the lower level, cluster-situated regulators (CSRs) directly control the transcription of neighboring genes within the gene cluster. Higher-level pleiotropic and global regulators exert their functions mainly through modulating the transcription of CSRs. Advances in understanding of the regulation of antibiotic biosynthesis in actinomycetes have inspired us to engineer these regulators for strain improvement and antibiotic discovery.

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          Most cited references 119

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          Discovery of microbial natural products by activation of silent biosynthetic gene clusters.

          Microorganisms produce a wealth of structurally diverse specialized metabolites with a remarkable range of biological activities and a wide variety of applications in medicine and agriculture, such as the treatment of infectious diseases and cancer, and the prevention of crop damage. Genomics has revealed that many microorganisms have far greater potential to produce specialized metabolites than was thought from classic bioactivity screens; however, realizing this potential has been hampered by the fact that many specialized metabolite biosynthetic gene clusters (BGCs) are not expressed in laboratory cultures. In this Review, we discuss the strategies that have been developed in bacteria and fungi to identify and induce the expression of such silent BGCs, and we briefly summarize methods for the isolation and structural characterization of their metabolic products.
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            Molecular regulation of antibiotic biosynthesis in streptomyces.

            Streptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific. Streptomyces coelicolor, the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis in S. coelicolor and other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism's physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerous Streptomyces genomes.
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              Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338.

              Saccharopolyspora erythraea is used for the industrial-scale production of the antibiotic erythromycin A, derivatives of which play a vital role in medicine. The sequenced chromosome of this soil bacterium comprises 8,212,805 base pairs, predicted to encode 7,264 genes. It is circular, like those of the pathogenic actinomycetes Mycobacterium tuberculosis and Corynebacterium diphtheriae, but unlike the linear chromosomes of the model actinomycete Streptomyces coelicolor A3(2) and the closely related Streptomyces avermitilis. The S. erythraea genome contains at least 25 gene clusters for production of known or predicted secondary metabolites, at least 72 genes predicted to confer resistance to a range of common antibiotic classes and many sets of duplicated genes to support its saprophytic lifestyle. The availability of the genome sequence of S. erythraea will improve insight into its biology and facilitate rational development of strains to generate high-titer producers of clinically important antibiotics.
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                Author and article information

                Contributors
                Journal
                Synth Syst Biotechnol
                Synth Syst Biotechnol
                Synthetic and Systems Biotechnology
                KeAi Publishing
                2405-805X
                2405-805X
                23 October 2018
                December 2018
                23 October 2018
                : 3
                : 4
                : 229-235
                Affiliations
                [a ]Biotechnology Research Center, Southwest University, Chongqing, 400715, China
                [b ]State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China
                [c ]Academy of Agricultural Sciences, Southwest University, Chongqing, 400715, China
                Author notes
                []Corresponding author. No.2 Tiansheng Road, Beibei District, Chongqing, 400715, China. niu062376@ 123456swu.edu.cn
                Article
                S2405-805X(18)30047-4
                10.1016/j.synbio.2018.10.005
                6215055
                © 2018 Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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