TY - JOUR A1 - Dehm, Daniel A1 - Krumbholz, Julia A1 - Baunach, Martin A1 - Wiebach, Vincent A1 - Hinrichs, Katrin A1 - Guljamow, Arthur A1 - Tabuchi, Takeshi A1 - Jenke-Kodama, Holger A1 - Süssmuth, Roderich D. A1 - Dittmann-Thünemann, Elke T1 - Unlocking the spatial control of secondary metabolism uncovers hidden natural product diversity in nostoc punctiforme JF - ACS chemical biology N2 - Filamentous cyanobacteria belong to the most prolific producers of structurally unique and biologically active natural products, yet the majority of biosynthetic gene clusters predicted for these multicellular collectives are currently orphan. Here, we present a systems analysis of secondary metabolite gene expression in the model strain Nostoc punctiforme PCC73102 using RNA-seq and fluorescence reporter analysis. Our data demonstrate that the majority of the cryptic gene clusters are not silent but are expressed with regular or sporadic pattern. Cultivation of N. punctiforme using high-density fermentation overrules the spatial control and leads to a pronounced upregulation of more than 50% of biosynthetic gene clusters. Our data suggest that a combination of autocrine factors, a high CO2 level, and high light account for the upregulation of individual pathways. Our overarching study not only sheds light on the strategies of filamentous cyanobacteria to share the enormous metabolic burden connected with the production of specialized molecules but provides an avenue for the genome-based discovery of natural products in multicellular cyanobacteria as exemplified by the discovery of highly unusual variants of the tricyclic peptide microviridin. Y1 - 2019 U6 - https://doi.org/10.1021/acschembio.9b00240 SN - 1554-8929 SN - 1554-8937 VL - 14 IS - 6 SP - 1271 EP - 1279 PB - American Chemical Society CY - Washington ER - TY - JOUR A1 - Ahmed, Muhammad N. A1 - Reyna-Gonzalez, Emmanuel A1 - Schmid, Bianca A1 - Wiebach, Vincent A1 - Suessmuth, Roderich D. A1 - Dittmann, Elke A1 - Fewer, David P. T1 - Phylogenomic Analysis of the Microviridin Biosynthetic Pathway Coupled with Targeted Chemo-Enzymatic Synthesis Yields Potent Protease Inhibitors JF - ACS chemical biology N2 - 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. Y1 - 2017 U6 - https://doi.org/10.1021/acschembio.7b00124 SN - 1554-8929 SN - 1554-8937 VL - 12 SP - 1538 EP - 1546 PB - American Chemical Society CY - Washington ER -