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Antibiotic Biosynthesis

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Huarong Tan – One of the best experts on this subject based on the ideXlab platform.

  • Specialised metabolites regulating Antibiotic Biosynthesis in Streptomyces spp.
    FEMS microbiology reviews, 2016
    Co-Authors: Guoqing Niu, Keith F. Chater, Yuqing Tian, Jihui Zhang, Huarong Tan


    Streptomyces bacteria are the major source of Antibiotics and other secondary metabolites. Various environmental and physiological conditions affect the onset and level of production of each Antibiotic by influencing concentrations of the ligands for conserved global regulatory proteins. In addition, as reviewed here, well-known autoregulators such as γ-butyrolactones, themselves products of secondary metabolism, accumulate late in growth to concentrations allowing their effective interaction with cognate binding proteins, in a necessary prelude to Antibiotic Biosynthesis. Most autoregulator binding proteins target the conserved global regulatory gene adpA, and/or regulatory genes for ‘cluster-situated regulators’ (CSRs) linked to Antibiotic biosynthetic gene clusters. It now appears that some CSRs bind intermediates and end products of Antibiotic Biosynthesis, with regulatory effects interwoven with those of autoregulators. These ligands can exert cross-pathway effects within producers of more than one Antibiotic, and when excreted into the extracellular environment may have population-wide effects on production, and mediate interactions with neighbouring microorganisms in natural communities, influencing speciation. Greater understanding of these autoregulatory and cross-regulatory activities may aid the discovery of new signalling molecules and their use in activating cryptic Antibiotic biosynthetic pathways.

  • molecular regulation of Antibiotic Biosynthesis in streptomyces
    Microbiology and Molecular Biology Reviews, 2013
    Co-Authors: Gang Liu, Guoqing Niu, Keith F. Chater, Govind Chandra, Huarong Tan


    SUMMARY 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 organism9s 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.

  • differential regulation of Antibiotic Biosynthesis by drar k a novel two component system in streptomyces coelicolor
    Molecular Microbiology, 2012
    Co-Authors: Hong Zhu, Huarong Tan, Fujun Dang, Weiwen Zhang, Zhongjun Qin, Sheng Yang, Weihong Jiang


    A novel two-component system (TCS) designated as DraR-K (sco3063/sco3062) was identified to be involved in differential regulation of Antibiotic Biosynthesis in Streptomyces coelicolor. The S. coelicolor mutants with deletion of either or both of draR and draK exhibited significantly reduced actinorhodin (ACT) but increased undecylprodigiosin (RED) production on minimal medium (MM) supplemented separately with high concentration of different nitrogen sources. These mutants also overproduced a yellow-pigmented type I polyketide (yCPK) on MM with glutamate (Glu). It was confirmed that DraR-K activates ACT but represses yCPK production directly through the pathway-specific activator genes actII-ORF4 and kasO, respectively, while its role on RED Biosynthesis was independent of pathway-specific activator genes redD/redZ. DNase I footprinting assays revealed that the DNA binding sites for DraR were at -124 to -98 nt and -24 to -1 nt relative to the respective transcription start point of actII-ORF4 and kasO. Comparison of the binding sites allowed the identification of a consensus DraR-binding sequence, 5′-AMAAWYMAKCA-3′ (M: A or C; W: A or T; Y: C or T; K: G or T). By genome screening and gel-retardation assay, 11 new targets of DraR were further identified in the genome of S. coelicolor. Functional analysis of these tentative targets revealed the involvement of DraR-K in primary metabolism. DraR-K homologues are widely spread in different streptomycetes. Interestingly, deletion of draR-Ksav (sav_3481/sav_3480, homologue of draR-K) in the industrial model strain S. avermitilis NRRL-8165 led to similar abnormal Antibiotic Biosynthesis, showing higher avermectin while slightly decreased oligomycin A production, suggesting that DraR-K-mediated regulation system might be conserved in streptomycetes. This study further reveals the complexity of TCS in regulation of Antibiotic Biosynthesis in Streptomyces.

Weihong Jiang – One of the best experts on this subject based on the ideXlab platform.

  • The orphan histidine kinase PdtaS-p regulates both morphological differentiation and Antibiotic Biosynthesis together with the orphan response regulator PdtaR-p in Streptomyces.
    Microbiological research, 2020
    Co-Authors: Yawei Zhao, Guosong Zheng, Hengnuo Tao, Jun Chen, Weihong Jiang


    In Streptomyces pristinaespiralis, the orphan histidine kinase (HK) PdtaS-p (encoded by SSDG_02492), which belongs to proteins of two-component systems (TCSs), plays an important role in both morphological differentiation and Antibiotic Biosynthesis. Owing to the isolated genetic organization of pdtaS-p, it is a challenge to identify its cognate response regulator (RR) and hampers the efforts to elucidate the regulation mechanism of PdtaS-p. In this study, based on bioinformatics analysis, we identify the cognate RR PdtaR-p (encoded by SSDG_04087) of PdtaS-p by phenotype similarity of gene deletion mutants as well as in vitro phosphor-transfer assay. We show that the mutants (ΔpdtaR-p and ΔpdtaS-p) exhibit almost the same phenotypical changes, showing a bald phenotype on MS agar and reduced pristinamycin Biosynthesis. Further phosphor-transfer assay indicates that the phosphoryl group of HK PdtaS-p can be specifically transferred to RR PdtaR-p. Compared with the majority of RRs that harbor DNA-binding domains, PdtaR-p contains a putative ANTAR RNA-binding domain involved in controlling gene expression at the post-transcription level. Finally, we demonstrate that their ortholog from the model strain Streptomyces coelicolor, PdtaS-c/PdtaR-c, also regulates both morphological differentiation and Antibiotics Biosynthesis, suggesting that PdtaS-p/PdtaR-p-mediated molecular regulation may be conserved in the genus Streptomyces. To our knowledge, this is the first report describing the functional identification of ANTAR RNA-binding regulators in Streptomyces.

  • Overexpression of the diguanylate cyclase CdgD blocks developmental transitions and Antibiotic Biosynthesis in Streptomyces coelicolor.
    Science China. Life sciences, 2019
    Co-Authors: Xiaocao Liu, Guosong Zheng, Gang Wang, Weihong Jiang


    Cyclic dimeric GMP (c-di-GMP) has emerged as the nucleotide second messenger regulating both development and Antibiotic production in high-GC, Gram-positive streptomycetes. Here, a diguanylate cyclase (DGC), CdgD, encoded by SCO5345 from the model strain Streptomyces coelicolor, was functionally identified and characterized to be involved in c-di-GMP synthesis through genetic and biochemical analysis. cdgD overexpression resulted in significantly reduced production of actinorhodin and undecylprodigiosin, as well as completely blocked sporulation or aerial mycelium formation on two different solid media. In the cdgD-overexpression strain, intracellular c-di-GMP levels were 13-27-fold higher than those in the wild-type strain. In vitro enzymatic assay demonstrated that CdgD acts as a DGC, which could efficiently catalyze the synthesis of c-di-GMP from two GTP molecules. Heterologous overproduction of cdgD in two industrial Streptomyces strains could similarly impair developmental transitions as well as Antibiotic Biosynthesis. Collectively, our results combined with previously reported data clearly demonstrated that c-di-GMP-mediated signalling pathway plays a central and universal role in the life cycle as well as secondary metabolism in streptomycetes.

  • A Novel Two-Component System, GluR-GluK, Involved in Glutamate Sensing and Uptake in Streptomyces coelicolor.
    Journal of bacteriology, 2017
    Co-Authors: Weihong Jiang


    Two-component systems (TCSs), the predominant signal transduction pathways employed by bacteria, play important roles in physiological metabolism in Streptomyces Here, a novel TCS, GluR-GluK (encoded by SCO5778-SCO5779), which is located divergently from the gluABCD operon encoding a glutamate uptake system, was identified as being involved in glutamate sensing and uptake as well as Antibiotic Biosynthesis in Streptomyces coelicolor Under the condition of minimal medium (MM) supplemented with different concentrations of glutamate, deletion of the gluR-gluK operon (gluR-K) resulted in enhanced actinorhodin (ACT) but reduced undecylprodigiosin (RED) and yellow type I polyketide (yCPK) production, suggesting that GluR-GluK plays a differential role in Antibiotic Biosynthesis. Furthermore, we found that the response regulator GluR directly promotes the expression of gluABCD under the culture condition of MM with a high concentration of glutamate (75 mM). Using the biolayer interferometry assay, we demonstrated that glutamate acts as the direct signal of the histidine kinase GluK. It was therefore suggested that upon sensing high concentrations of glutamate, GluR-GluK would be activated and thereby facilitate glutamate uptake by increasing gluABCD expression. Finally, we demonstrated that the role of GluR-GluK in Antibiotic Biosynthesis is independent of its function in glutamate uptake. Considering the wide distribution of the glutamate-sensing (GluR-GluK) and uptake (GluABCD) module in actinobacteria, it could be concluded that the GluR-GluK signal transduction pathway involved in secondary metabolism and glutamate uptake should be highly conserved in this bacterial phylum.IMPORTANCE In this study, a novel two-component system (TCS), GluR-GluK, was identified to be involved in glutamate sensing and uptake as well as Antibiotic Biosynthesis in Streptomyces coelicolor A possible GluR-GluK working model was proposed. Upon sensing high glutamate concentrations (such as 75 mM), activated GluR-GluK could regulate both glutamate uptake and Antibiotic Biosynthesis. However, under a culture condition of MM supplemented with low concentrations of glutamate (such as 10 mM), although GluR-GluK is activated, its activity is sufficient only for the regulation of Antibiotic Biosynthesis. To the best of our knowledge, this is the first report describing a TCS signal transduction pathway for glutamate sensing and uptake in actinobacteria.

Charles J. Thompson – One of the best experts on this subject based on the ideXlab platform.

  • Pleiotropic Functions of a Streptomyces pristinaespiralis Autoregulator Receptor in Development, Antibiotic Biosynthesis, and Expression of a Superoxide Dismutase
    The Journal of biological chemistry, 2001
    Co-Authors: Marc Folcher, Hélène Gaillard, Lieu T. Nguyen, Kien T. Nguyen, Patricia Lacroix, Nathalie Bamas-jacques, Monique Rinkel, Charles J. Thompson


    Abstract In Streptomyces, a family of related butyrolactones and their corresponding receptor proteins serve as quorum-sensing systems that can activate morphological development and Antibiotic Biosynthesis. Streptomyces pristinaespiraliscontains a gene cluster encoding enzymes and regulatory proteins for the Biosynthesis of pristinamycin, a clinically important streptogramin Antibiotic complex. One of these proteins, PapR1, belongs to a well known family of Streptomyces Antibiotic regulatory proteins. Gel shift assays using crude cytoplasmic extracts detected SpbR, a developmentally regulated protein that bound to thepapR1 promoter. SpbR was purified, and its gene was cloned using reverse genetics. spbR encoded a 25-kDa protein similar to Streptomyces autoregulatory proteins of the butyrolactone receptor family, including scbR fromStreptomyces coelicolor. In Escherichia coli, purified SpbR and ScbR produced bound sequences immediately upstream ofpapR1, spbR, and scbR. SpbR DNA-binding activity was inhibited by an extracellular metabolite with chromatographic properties similar to those of the well known γ-butyrolactone signaling compounds. DNase I protection assays mapped the SpbR-binding site in the papR1 promoter to a sequence homologous to other known butyrolactone autoregulatory elements. A nucleotide data base search showed that these binding motifs were primarily located upstream of genes encoding StreptomycesAntibiotic regulatory proteins and butyrolactone receptors in variousStreptomyces species. Disruption of the spbRgene in S. pristinaespiralis resulted in severe defects in growth, morphological differentiation, pristinamycin Biosynthesis, and expression of a secreted superoxide dismutase.

  • Role of acid metabolism in Streptomyces coelicolor morphological differentiation and Antibiotic Biosynthesis.
    Journal of bacteriology, 2001
    Co-Authors: Patrick H. Viollier, Wolfgang Minas, Glenn E. Dale, Marc Folcher, Charles J. Thompson


    Studies of citrate synthase (CitA) were carried out to investigate its role in morphological development and Biosynthesis of Antibiotics in Streptomyces coelicolor. Purification of CitA, the major vegetative enzyme activity, allowed characterization of its kinetic properties. The apparent Km values of CitA for acetyl coenzyme A (acetyl-CoA) (32 μM) and oxaloacetate (17 μM) were similar to those of citrate synthases from other gram-positive bacteria and eukaryotes. CitA was not strongly inhibited by various allosteric feedback inhibitors (NAD+, NADH, ATP, ADP, isocitrate, or α-ketoglutarate). The corresponding gene (citA) was cloned and sequenced, allowing construction of a citA mutant (BZ2). BZ2 was a glutamate auxotroph, indicating that citA encoded the major citrate synthase allowing flow of acetyl-CoA into the tricarboxylic acid (TCA) cycle. Interruption of aerobic TCA cycle-based metabolism resulted in acidification of the medium and defects in morphological differentiation and Antibiotic Biosynthesis. These developmental defects of the citA mutant were in part due to a glucose-dependent medium acidification that was also exhibited by some other bald mutants. Unlike other acidogenic bald strains, citA and bldJ mutants were able to produce aerial mycelia and pigments when the medium was buffered sufficiently to maintain neutrality. Extracellular complementation studies suggested that citA defines a new stage of the Streptomyces developmental cascade.

  • Pleiotropic effects of cAMP on germination, Antibiotic Biosynthesis and morphological development in Streptomyces coelicolor
    Molecular microbiology, 1998
    Co-Authors: Urs Süsstrunk, Josette Pidoux, Stefan Taubert, Agnes Ullmann, Charles J. Thompson


    In wild-type Streptomyces coelicolor MT1110 cultures, cyclic adenosine 3′,5′ monophosphate (cAMP) was synthesized throughout the developmental programme with peaks of accumulation both during germination and later when aerial mycelium and actinorhodin were being produced. Construction and characterization of an adenylate cyclase disruption mutant (BZ1) demonstrated that cAMP facilitated these developmental processes. Although pulse-labelling experiments showed that a similar germination process was initiated in BZ1 and MT1110, germ-tube emergence was severely delayed in BZ1 and never occurred in more than 85% of the spores. Studies of growth and development on solid glucose minimal medium (SMMS, buffered or unbuffered) showed that MT1110 and BZ1 produced acid during the first rapid growth phase, which generated substrate mycelium. Thereafter, on unbuffered SMMS, only MT1110 resumed growth and produced aerial mycelium by switching to an alternative metabolism that neutralized its medium, probably by reincorporating and metabolizing extracellular acids. BZ1 was not able to neutralize its medium or produce aerial mycelium on unbuffered SMMS; these defects were suppressed by high concentrations (>1 mM) of cAMP during early growth or on buffered medium. Other developmental mutants (bldA, bldB, bldC, bldD, bldG) also irreversibly acidified this medium. However, these bald mutants were not suppressed by exogenous cAMP or neutralizing buffer. BZ1 also differentiated when it was cultured in close proximity to MT1110, a property observed in cross-feeding experiments between bald mutants and commonly thought to reflect diffusion of a discrete positively acting signalling molecule. In this case, MT1110 generated a more neutral pH environment that allowed BZ1 to reinitiate growth and form aerial mycelium. The fact that actinorhodin synthesis could be induced by concentrations of cAMP (< 20 microM) found in the medium of MT1110 cultures, suggested that it may serve as a diffusible signalling molecule to co-ordinate Antibiotic Biosynthesis.