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      The Inhibition of Antibiotic Production in Streptomyces coelicolor Over-Expressing the TetR Regulator SCO3201 IS Correlated With Changes in the Lipidome of the Strain

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          Abstract

          In condition of over-expression, SCO3201, a regulator of the TetR family was previously shown to strongly inhibit antibiotic production and morphological differentiation in Streptomyces coelicolor M145. In order to elucidate the molecular processes underlying this interesting, but poorly understood phenomenon, a comparative analysis of the lipidomes and transcriptomes of the strain over-expressing sco3201 and of the control strain containing the empty plasmid, was carried out. This study revealed that the strain over-expressing sco3201 had a higher triacylglycerol content and a lower phospholipids content than the control strain. This was correlated with up- and down- regulation of some genes involved in fatty acids biosynthesis ( fab) and degradation ( fad) respectively, indicating a direct or indirect control of the expression of these genes by SCO3201. In some instances, indirect control might involve TetR regulators, whose encoding genes present in close vicinity of genes involved in lipid metabolism, were shown to be differentially expressed in the two strains. Direct interaction of purified His 6-SCO3201 with the promoter regions of four of such TetR regulators encoding genes ( sco0116, sco0430, sco4167, and sco6792) was demonstrated. Furthermore, fasR ( sco2386), encoding the activator of the main fatty acid biosynthetic operon, sco2386- sco2390, has been shown to be an illegitimate positive regulatory target of SCO3201. Altogether our data demonstrated that the sco3201 over-expressing strain accumulates TAG and suggested that degradation of fatty acids was reduced in this strain. This is expected to result into a reduced acetyl-CoA availability that would impair antibiotic biosynthesis either directly or indirectly.

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          Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2).

          Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.
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            The thioredoxin antioxidant system.

            The thioredoxin (Trx) system, which is composed of NADPH, thioredoxin reductase (TrxR), and thioredoxin, is a key antioxidant system in defense against oxidative stress through its disulfide reductase activity regulating protein dithiol/disulfide balance. The Trx system provides the electrons to thiol-dependent peroxidases (peroxiredoxins) to remove reactive oxygen and nitrogen species with a fast reaction rate. Trx antioxidant functions are also shown by involvement in DNA and protein repair by reducing ribonucleotide reductase, methionine sulfoxide reductases, and regulating the activity of many redox-sensitive transcription factors. Moreover, Trx systems play critical roles in the immune response, virus infection, and cell death via interaction with thioredoxin-interacting protein. In mammalian cells, the cytosolic and mitochondrial Trx systems, in which TrxRs are high molecular weight selenoenzymes, together with the glutathione-glutaredoxin (Grx) system (NADPH, glutathione reductase, GSH, and Grx) control the cellular redox environment. Recently mammalian thioredoxin and glutathione systems have been found to be able to provide the electrons crossly and to serve as a backup system for each other. In contrast, bacteria TrxRs are low molecular weight enzymes with a structure and reaction mechanism distinct from mammalian TrxR. Many bacterial species possess specific thiol-dependent antioxidant systems, and the significance of the Trx system in the defense against oxidative stress is different. Particularly, the absence of a GSH-Grx system in some pathogenic bacteria such as Helicobacter pylori, Mycobacterium tuberculosis, and Staphylococcus aureus makes the bacterial Trx system essential for survival under oxidative stress. This provides an opportunity to kill these bacteria by targeting the TrxR-Trx system. Copyright © 2013 Elsevier Inc. All rights reserved.
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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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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                23 June 2020
                2020
                : 11
                : 1399
                Affiliations
                [1] 1Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institutes, Department of Ecology, School of Life Sciences and Technology, Engineering Research Center of Tropical and Subtropical Aquatic Ecological Engineering, Ministry of Education, Institute of Hydrobiology, Jinan University , Guangzhou, China
                [2] 2Université Paris-Saclay, Lipides, Systèmes Analytiques et Biologiques , Châtenay-Malabry, France
                [3] 3Group “Energetic Metabolism of Streptomyces”, Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, INRA, University Paris-Saclay , Gif-sur-Yvette, France
                Author notes

                Edited by: Haike Antelmann, Freie Universität Berlin, Germany

                Reviewed by: Yvonne Mast, German Collection of Microorganisms and Cell Cultures GmbH (DSMZ), Germany; Ramón I. Santamaría, Consejo Superior de Investigaciones Científicas (CSIC), Spain

                *Correspondence: Qizhong Zhang, zhangqzdr@ 123456126.com

                These authors have contributed equally to this work

                This article was submitted to Microbial Physiology and Metabolism, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2020.01399
                7324645
                fb6b962a-72f0-4493-baaa-e9b3a1c1b2c8
                Copyright © 2020 Zhang, Liang, Xu, Cui, Zhang, Abreu, David, Lejeune, Chaminade, Virolle and Xu.

                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) and the copyright owner(s) 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
                : 11 April 2020
                : 29 May 2020
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 64, Pages: 15, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Funded by: Natural Science Foundation of Guangdong Province 10.13039/501100003453
                Award ID: 2019A1515011791
                Award ID: 2019A1515012112
                Award ID: 2018A030313578
                Funded by: Centre National de la Recherche Scientifique 10.13039/501100004794
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                streptomyces coelicolor,antibiotics,tetr regulator,fatty acid metabolism,rna-seq

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