@article{AhmedReynaGonzalezSchmidetal.2017, author = {Ahmed, Muhammad N. and Reyna-Gonzalez, Emmanuel and Schmid, Bianca and Wiebach, Vincent and Suessmuth, Roderich D. and Dittmann, Elke and Fewer, David P.}, title = {Phylogenomic Analysis of the Microviridin Biosynthetic Pathway Coupled with Targeted Chemo-Enzymatic Synthesis Yields Potent Protease Inhibitors}, series = {ACS chemical biology}, volume = {12}, journal = {ACS chemical biology}, publisher = {American Chemical Society}, address = {Washington}, issn = {1554-8929}, doi = {10.1021/acschembio.7b00124}, pages = {1538 -- 1546}, year = {2017}, abstract = {Natural products and their semisynthetic derivatives are an important source of drugs for the pharmaceutical industry. Bacteria are prolific producers of natural products and encode a vast diversity of natural product biosynthetic gene clusters. However, much of this diversity is inaccessible to natural product discovery. Here, we use a combination of phylogenomic analysis of the microviridin biosynthetic pathway and chemo-enzymatic synthesis of bioinformatically predicted microviridins to yield new protease inhibitors. Phylogenomic analysis demonstrated that microviridin biosynthetic gene clusters occur across the bacterial domain and encode three distinct subtypes of precursor peptides. Our analysis shed light on the evolution of microviridin biosynthesis and enabled prioritization of their chemo-enzymatic production. Targeted one-pot synthesis of four microviridins encoded by the cyanobacterium Cyanothece sp. PCC 7822 identified a set of novel and potent serine protease inhibitors, the most active of which had an IC50 value of 21.5 nM. This study advances the genome mining techniques available for natural product discovery and obviates the need to culture bacteria.}, language = {en} } @misc{DittmannThuenemannGuggerSivonenetal.2015, author = {Dittmann-Th{\"u}nemann, Elke and Gugger, Muriel and Sivonen, Kaarina and Fewer, David P.}, title = {Natural Product Biosynthetic Diversity and Comparative Genomics of the Cyanobacteria}, series = {Trends in microbiology}, volume = {23}, journal = {Trends in microbiology}, number = {10}, publisher = {Elsevier}, address = {Oxford}, issn = {0966-842X}, doi = {10.1016/j.tim.2015.07.008}, pages = {642 -- 652}, year = {2015}, abstract = {Cyanobacteria are an ancient lineage of slow-growing photosynthetic bacteria and a prolific source of natural products with intricate chemical structures and potent biological activities. The bulk of these natural products are known from just a handful of genera. Recent efforts have elucidated the mechanisms underpinning the biosynthesis of a diverse array of natural products from cyanobacteria. Many of the biosynthetic mechanisms are unique to cyanobacteria or rarely described from other organisms. Advances in genome sequence technology have precipitated a deluge of genome sequences for cyanobacteria. This makes it possible to link known natural products to biosynthetic gene clusters but also accelerates the discovery of new natural products through genome mining. These studies demonstrate that cyanobacteria encode a huge variety of cryptic gene clusters for the production of natural products, and the known chemical diversity is likely to be just a fraction of the true biosynthetic capabilities of this fascinating and ancient group of organisms.}, language = {en} } @article{VossBolhuisFeweretal.2013, author = {Voss, Bj{\"o}rn and Bolhuis, Henk and Fewer, David P. and Kopf, Matthias and M{\"o}ke, Fred and Haas, Fabian and El-Shehawy, Rehab and Hayes, Paul and Bergman, Birgitta and Sivonen, Kaarina and Dittmann-Th{\"u}nemann, Elke and Scanlan, Dave J. and Hagemann, Martin and Stal, Lucas J. and Hess, Wolfgang R.}, title = {Insights into the physiology and ecology of the brackish-water-adapted cyanobacterium nodularia spumigena CCY9414 based on a genome-transcriptome analysis}, series = {PLoS one}, volume = {8}, journal = {PLoS one}, number = {3}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0060224}, pages = {22}, year = {2013}, abstract = {Nodularia spumigena is a filamentous diazotrophic cyanobacterium that dominates the annual late summer cyanobacterial blooms in the Baltic Sea. But N. spumigena also is common in brackish water bodies worldwide, suggesting special adaptation allowing it to thrive at moderate salinities. A draft genome analysis of N. spumigena sp. CCY9414 yielded a single scaffold of 5,462,271 nucleotides in length on which genes for 5,294 proteins were annotated. A subsequent strand-specific transcriptome analysis identified more than 6,000 putative transcriptional start sites (TSS). Orphan TSSs located in intergenic regions led us to predict 764 non-coding RNAs, among them 70 copies of a possible retrotransposon and several potential RNA regulators, some of which are also present in other N2-fixing cyanobacteria. Approximately 4\% of the total coding capacity is devoted to the production of secondary metabolites, among them the potent hepatotoxin nodularin, the linear spumigin and the cyclic nodulapeptin. The transcriptional complexity associated with genes involved in nitrogen fixation and heterocyst differentiation is considerably smaller compared to other Nostocales. In contrast, sophisticated systems exist for the uptake and assimilation of iron and phosphorus compounds, for the synthesis of compatible solutes, and for the formation of gas vesicles, required for the active control of buoyancy. Hence, the annotation and interpretation of this sequence provides a vast array of clues into the genomic underpinnings of the physiology of this cyanobacterium and indicates in particular a competitive edge of N. spumigena in nutrient-limited brackish water ecosystems.}, language = {en} } @misc{DittmannThuenemannFewerNeilan2013, author = {Dittmann-Th{\"u}nemann, Elke and Fewer, David P. and Neilan, Brett A.}, title = {Cyanobacterial toxins biosynthetic routes and evolutionary roots}, series = {FEMS microbiology reviews}, volume = {37}, journal = {FEMS microbiology reviews}, number = {1}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {0168-6445}, doi = {10.1111/j.1574-6976.2012.12000.x}, pages = {23 -- 43}, year = {2013}, abstract = {Cyanobacteria produce an unparalleled variety of toxins that can cause severe health problems or even death in humans, and wild or domestic animals. In the last decade, biosynthetic pathways have been assigned to the majority of the known toxin families. This review summarizes current knowledge about the enzymatic basis for the production of the hepatotoxins microcystin and nodularin, the cytotoxin cylindrospermopsin, the neurotoxins anatoxin and saxitoxin, and the dermatotoxin lyngbyatoxin. Elucidation of the biosynthetic pathways of the toxins has paved the way for the development of molecular techniques for the detection and quantification of the producing cyanobacteria in different environments. Phylogenetic analyses of related clusters from a large number of strains has also allowed for the reconstruction of the evolutionary scenarios that have led to the emergence, diversification, and loss of such gene clusters in different strains and genera of cyanobacteria. Advances in the understanding of toxin biosynthesis and evolution have provided new methods for drinking-water quality control and may inspire the development of techniques for the management of bloom formation in the future.}, language = {en} }