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Activation of silent gene cluster

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https://www.readbyqxmd.com/read/28513710/are-highly-morphed-peptide-frameworks-lurking-silently-in-microbial-genomes-valuable-as-next-generation-antibiotic-scaffolds
#1
Christopher T Walsh
Antibiotics are a therapeutic class that, once deployed, select for resistant bacterial pathogens and so shorten their useful life cycles. As a consequence new versions of antibiotics are constantly needed. Among the antibiotic natural products, morphed peptide scaffolds, converting conformationally mobile, short-lived linear peptides into compact, rigidified small molecule frameworks, act on a wide range of bacterial targets. Advances in bacterial genome mining, biosynthetic gene cluster prediction and expression, and mass spectroscopic structure analysis suggests many more peptides, modified both in side chains and peptide backbones, await discovery...
May 17, 2017: Natural Product Reports
https://www.readbyqxmd.com/read/28451290/activation-and-characterization-of-a-cryptic-gene-cluster-reveals-a-cyclization-cascade-for-polycyclic-tetramate-macrolactams
#2
Subhasish Saha, Wenjun Zhang, Guangtao Zhang, Yiguang Zhu, Yuchan Chen, Wei Liu, Chengshan Yuan, Qingbo Zhang, Haibo Zhang, Liping Zhang, Weimin Zhang, Changsheng Zhang
Polycyclic tetramate macrolactams (PTMs) are a growing class of natural products and are derived from a hybrid polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS) pathway. PTM biosynthetic gene clusters are conserved and widely distributed in bacteria, however, most of them remain silent. Herein we report the activation of a PTM gene cluster in marine-derived Streptomyces pactum SCSIO 02999 by promoter engineering and heterologous expression, leading to the discovery of six new PTMs, pactamides A-F (11-16), with potent cytotoxic activity upon several human cancer cell lines...
February 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28442735/novel-antibiotic-screening-methods-to-awaken-silent-or-cryptic-secondary-metabolic-pathways-in-actinomycetes
#3
REVIEW
Hiroyasu Onaka
Streptomyces have the potential to produce more than 30 secondary metabolites; however, the expression of most metabolite biosynthetic gene clusters is cryptic or silent. Indeed, the expression of these genes is conditional and dependent on culture conditions. To activate such gene clusters, many methods have been developed. In this review, I describe two activation approaches developed in my laboratory: use of the activation mediator goadsporin and combined-culture. Goadsporin is a chemical substance isolated from Streptomyces sp...
April 26, 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28398287/crispr-cas9-strategy-for-activation-of-silent-streptomyces-biosynthetic-gene-clusters
#4
Mingzi M Zhang, Fong Tian Wong, Yajie Wang, Shangwen Luo, Yee Hwee Lim, Elena Heng, Wan Lin Yeo, Ryan E Cobb, Behnam Enghiad, Ee Lui Ang, Huimin Zhao
Here we report an efficient CRISPR-Cas9 knock-in strategy to activate silent biosynthetic gene clusters (BGCs) in streptomycetes. We applied this one-step strategy to activate multiple BGCs of different classes in five Streptomyces species and triggered the production of unique metabolites, including a novel pentangular type II polyketide in Streptomyces viridochromogenes. This potentially scalable strategy complements existing activation approaches and facilitates discovery efforts to uncover new compounds with interesting bioactivities...
April 10, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28379186/establishment-of-the-inducible-tet-on-system-for-the-activation-of-the-silent-trichosetin-gene-cluster-in-fusarium-fujikuroi
#5
Slavica Janevska, Birgit Arndt, Leonie Baumann, Lisa Helene Apken, Lucas Maciel Mauriz Marques, Hans-Ulrich Humpf, Bettina Tudzynski
The PKS-NRPS-derived tetramic acid equisetin and its N-desmethyl derivative trichosetin exhibit remarkable biological activities against a variety of organisms, including plants and bacteria, e.g., Staphylococcus aureus. The equisetin biosynthetic gene cluster was first described in Fusarium heterosporum, a species distantly related to the notorious rice pathogen Fusarium fujikuroi. Here we present the activation and characterization of a homologous, but silent, gene cluster in F. fujikuroi. Bioinformatic analysis revealed that this cluster does not contain the equisetin N-methyltransferase gene eqxD and consequently, trichosetin was isolated as final product...
April 5, 2017: Toxins
https://www.readbyqxmd.com/read/28360891/cloning-and-heterologous-expression-of-a-large-sized-natural-product-biosynthetic-gene-cluster-in-streptomyces-species
#6
REVIEW
Hee-Ju Nah, Hye-Rim Pyeon, Seung-Hoon Kang, Si-Sun Choi, Eung-Soo Kim
Actinomycetes family including Streptomyces species have been a major source for the discovery of novel natural products (NPs) in the last several decades thanks to their structural novelty, diversity and complexity. Moreover, recent genome mining approach has provided an attractive tool to screen potentially valuable NP biosynthetic gene clusters (BGCs) present in the actinomycetes genomes. Since many of these NP BGCs are silent or cryptic in the original actinomycetes, various techniques have been employed to activate these NP BGCs...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28358596/endophytic-actinobacteria-diversity-secondary-metabolism-and-mechanisms-to-unsilence-biosynthetic-gene-clusters
#7
Raghavan Dinesh, Veeraraghavan Srinivasan, Sheeja T E, Muthuswamy Anandaraj, Hamza Srambikkal
Endophytic actinobacteria, which reside in the inner tissues of host plants, are gaining serious attention due to their capacity to produce a plethora of secondary metabolites (e.g. antibiotics) possessing a wide variety of biological activity with diverse functions. This review encompasses the recent reports on endophytic actinobacterial species diversity, in planta habitats and mechanisms underlying their mode of entry into plants. Besides, their metabolic potential, novel bioactive compounds they produce and mechanisms to unravel their hidden metabolic repertoire by activation of cryptic or silent biosynthetic gene clusters (BGCs) for eliciting novel secondary metabolite production are discussed...
March 30, 2017: Critical Reviews in Microbiology
https://www.readbyqxmd.com/read/28320949/discovery-of-scmr-as-a-global-regulator-of-secondary-metabolism-and-virulence-in-burkholderia-thailandensis-e264
#8
Dainan Mao, Leah B Bushin, Kyuho Moon, Yihan Wu, Mohammad R Seyedsayamdost
Bacteria produce a diverse array of secondary metabolites that have been invaluable in the clinic and in research. These metabolites are synthesized by dedicated biosynthetic gene clusters (BGCs), which assemble architecturally complex molecules from simple building blocks. The majority of BGCs in a given bacterium are not expressed under normal laboratory growth conditions, and our understanding of how they are silenced is in its infancy. Here, we have addressed this question in the Gram-negative model bacterium Burkholderia thailandensis E264 using genetic, transcriptomic, metabolomic, and chemical approaches...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28288336/breaking-the-silence-new-strategies-for-discovering-novel-natural-products
#9
REVIEW
Hengqian Ren, Bin Wang, Huimin Zhao
Natural products have been a prolific source of antibacterial and anticancer drugs for decades. One of the major challenges in natural product discovery is that the vast majority of natural product biosynthetic gene clusters (BGCs) have not been characterized, partially due to the fact that they are either transcriptionally silent or expressed at very low levels under standard laboratory conditions. Here we describe the strategies developed in recent years (mostly between 2014-2016) for activating silent BGCs...
March 10, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28270798/wide-distribution-of-foxicin-biosynthetic-gene-clusters-in-streptomyces-strains-an-unusual-secondary-metabolite-with-various-properties
#10
Anja Greule, Marija Marolt, Denise Deubel, Iris Peintner, Songya Zhang, Claudia Jessen-Trefzer, Christian De Ford, Sabrina Burschel, Shu-Ming Li, Thorsten Friedrich, Irmgard Merfort, Steffen Lüdeke, Philippe Bisel, Michael Müller, Thomas Paululat, Andreas Bechthold
Streptomyces diastatochromogenes Tü6028 is known to produce the polyketide antibiotic polyketomycin. The deletion of the pokOIV oxygenase gene led to a non-polyketomycin-producing mutant. Instead, novel compounds were produced by the mutant, which have not been detected before in the wild type strain. Four different compounds were identified and named foxicins A-D. Foxicin A was isolated and its structure was elucidated as an unusual nitrogen-containing quinone derivative using various spectroscopic methods...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28221784/development-of-a-biosensor-concept-to-detect-the-production-of-cluster-specific-secondary-metabolites
#11
Yi-Qian Sun, Tobias Busche, Christian Rückert, Constanze Paulus, Yuriy Rebets, Renata Novakova, Joern Kalinowski, Andriy Luzhetskyy, Jan Kormanec, Olga N Sekurova, Sergey B Zotchev
Genome mining of actinomycete bacteria aims at the discovery of novel bioactive secondary metabolites that can be developed into drugs. A new repressor-based biosensor to detect activated secondary metabolite biosynthesis gene clusters in Streptomyces was developed. Biosynthetic gene clusters for undecylprodigiosin and coelimycin in the genome of Streptomyces lividans TK24, which encoded TetR-like repressors and appeared to be almost "silent" based on the RNA-seq data were chosen for the proof-of-principle studies...
February 21, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28218529/antibacterial-paramagnetic-quinones-from-actinoallomurus
#12
Marianna Iorio, João Cruz, Matteo Simone, Alice Bernasconi, Cristina Brunati, Margherita Sosio, Stefano Donadio, Sonia I Maffioli
Four metabolites, designated paramagnetoquinone A, B, C, and D (1-4), were isolated from three strains belonging to the actinomycete genus Actinoallomurus. Compounds 1 and 2 showed potent antibacterial activity with MIC values lower than 0.015 μg/mL against Gram-positive pathogens, including antibiotic-resistant strains. Since compounds 1 and 2 were NMR-silent due to the presence of an oxygen radical, structure elucidation was achieved through a combination of derivatizations, oxidations, and analysis of (13)C-labeled compounds...
February 20, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28143937/screen-for-reactivation-of-mecp2-on-the-inactive-x-chromosome-identifies-the-bmp-tgf-%C3%AE-superfamily-as-a-regulator-of-xist-expression
#13
Smitha Sripathy, Vid Leko, Robin L Adrianse, Taylor Loe, Eric J Foss, Emily Dalrymple, Uyen Lao, Tonibelle Gatbonton-Schwager, Kelly T Carter, Bernhard Payer, Patrick J Paddison, William M Grady, Jeannie T Lee, Marisa S Bartolomei, Antonio Bedalov
Rett syndrome (RS) is a debilitating neurological disorder affecting mostly girls with heterozygous mutations in the gene encoding the methyl-CpG-binding protein MeCP2 on the X chromosome. Because restoration of MeCP2 expression in a mouse model reverses neurologic deficits in adult animals, reactivation of the wild-type copy of MeCP2 on the inactive X chromosome (Xi) presents a therapeutic opportunity in RS. To identify genes involved in MeCP2 silencing, we screened a library of 60,000 shRNAs using a cell line with a MeCP2 reporter on the Xi and found 30 genes clustered in seven functional groups...
February 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28103011/discovery-of-a-phosphonoacetic-acid-derived-natural-product-by-pathway-refactoring
#14
Todd S Freestone, Kou-San Ju, Bin Wang, Huimin Zhao
The activation of silent natural product gene clusters is a synthetic biology problem of great interest. As the rate at which gene clusters are identified outpaces the discovery rate of new molecules, this unknown chemical space is rapidly growing, as too are the rewards for developing technologies to exploit it. One class of natural products that has been underrepresented is phosphonic acids, which have important medical and agricultural uses. Hundreds of phosphonic acid biosynthetic gene clusters have been identified encoding for unknown molecules...
January 23, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28062460/large-scale-transposition-mutagenesis-of-streptomyces-coelicolor-identifies-hundreds-of-genes-influencing-antibiotic-biosynthesis
#15
Zhong Xu, Yemin Wang, Keith F Chater, Hong-Yu Ou, H Howard Xu, Zixin Deng, Meifeng Tao
Gram-positive Streptomyces bacteria produce thousands of bioactive secondary metabolites, including antibiotics. To systematically investigate genes affecting secondary metabolism, we developed a hyperactive transposase-based Tn5 transposition system and employed it to mutagenize the model species Streptomyces coelicolor, leading to the identification of 51,443 transposition insertions. These insertions were distributed randomly along the chromosome except for some preferred regions associated with relatively low GC content in the chromosomal core...
March 15, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/27981234/coordinate-regulation-of-antimycin-and-candicidin-biosynthesis
#16
Thomas C McLean, Paul A Hoskisson, Ryan F Seipke
Streptomyces species produce an incredible array of high-value specialty chemicals and medicinal therapeutics. A single species typically harbors ~30 biosynthetic pathways, but only a few them are expressed in the laboratory; thus, poor understanding of how natural-product biosynthesis is regulated is a major bottleneck in drug discovery. Antimycins are a large family of anticancer compounds widely produced by Streptomyces species, and their regulation is atypical compared to that of most other natural products...
November 2016: MSphere
https://www.readbyqxmd.com/read/27730337/stress-driven-discovery-of-a-cryptic-antibiotic-produced-by-streptomyces-sp-wu20-from-kueishantao-hydrothermal-vent-with-an-integrated-metabolomics-strategy
#17
Yutong Shi, Chengqian Pan, Bibi Nazia Auckloo, Xuegang Chen, Chen-Tung Arthur Chen, Kuiwu Wang, Xiaodan Wu, Ying Ye, Bin Wu
Marine hydrothermal microorganisms respond rapidly to the changes in the concentrations and availability of metals within hydrothermal vent microbial habitats which are strongly influenced by elevated levels of heavy metals. Most hydrothermal vent actinomycetes possess a remarkable capability for the synthesis of a broad variety of biologically active secondary metabolites. Major challenges in the screening of these microorganisms are to activate the expression of cryptic biosynthetic gene clusters and the development of technologies for efficient dereplication of known compounds...
February 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/27695614/expression-profile-of-developmentally-important-genes-in-preand-peri-implantation-goat-embryos-produced-in-vitro
#18
Pouria HosseinNia, Mehdi Hajian, Mojtaba Tahmoorespur, Sayyed Morteza Hosseini, Somayyeh Ostadhosseini, Mohammad Reza Nasiri, Mohammad Hossein Nasr-Esfahani
BACKGROUND: Little is understood about the regulation of gene expression during early goat embryo development. This study investigated the expression profile of 19 genes, known to be critical for early embryo development in mouse and human, at five different stages of goat in vitro embryo development (oocyte, 8-16 cell, morula, day-7 blastocyst, and day 14 blastocyst). MATERIALS AND METHODS: In this experimental study, stage-specific profiling using real time-quantitative polymerase chain reaction (RT-qPCR) revealed robust and dynamic patterns of stage-specific gene activity that fall into four major clusters depending on their respective mRNA profiles...
October 2016: International Journal of Fertility & Sterility
https://www.readbyqxmd.com/read/27621770/chromatin-boundary-elements-organize-genomic-architecture-and-developmental-gene-regulation-in-drosophila-hox-clusters
#19
REVIEW
Zhibo Ma, Mo Li, Sharmila Roy, Kevin J Liu, Matthew L Romine, Derrick C Lane, Sapna K Patel, Haini N Cai
The three-dimensional (3D) organization of the eukaryotic genome is critical for its proper function. Evidence suggests that extensive chromatin loops form the building blocks of the genomic architecture, separating genes and gene clusters into distinct functional domains. These loops are anchored in part by a special type of DNA elements called chromatin boundary elements (CBEs). CBEs were originally found to insulate neighboring genes by blocking influences of transcriptional enhancers or the spread of silent chromatin...
August 26, 2016: World Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27618884/new-deferoxamine-glycoconjugates-produced-upon-overexpression-of-pathway-specific-regulatory-gene-in-the-marine-sponge-derived-streptomyces-albus-pva94-07
#20
Olga N Sekurova, Ignacio Pérez-Victoria, Jesús Martín, Kristin F Degnes, Håvard Sletta, Fernando Reyes, Sergey B Zotchev
Activation of silent biosynthetic gene clusters in Streptomyces bacteria via overexpression of cluster-specific regulatory genes is a promising strategy for the discovery of novel bioactive secondary metabolites. This approach was used in an attempt to activate a cryptic gene cluster in a marine sponge-derived Streptomyces albus PVA94-07 presumably governing the biosynthesis of peptide-based secondary metabolites. While no new peptide-based metabolites were detected in the recombinant strain, it was shown to produce at least four new analogues of deferoxamine with additional acyl and sugar moieties, for which chemical structures were fully elucidated...
August 27, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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