title: Effects of Halide Ions on the Carbamidocyclophane Biosynthesis in Nostoc sp. CAVN2.
abstract: In this study, the influence of halide ions on [7.7]paracyclophane biosynthesis in the cyanobacterium Nostoc sp. CAVN2 was investigated. In contrast to KI and KF, supplementation of the culture medium with KCl or KBr resulted not only in an increase of growth but also in an up-regulation of carbamidocyclophane production. LC-MS analysis indicated the presence of chlorinated, brominated, but also non-halogenated derivatives. In addition to 22 known cylindrocyclophanes and carbamidocyclophanes, 27 putative congeners have been detected. Nine compounds, carbamidocyclophanes M-U, were isolated, and their structural elucidation by 1D and 2D NMR experiments in combination with HRMS and ECD analysis revealed that they are brominated analogues of chlorinated carbamidocyclophanes. Quantification of the carbamidocyclophanes showed that chloride is the preferably utilized halide, but incorporation is reduced in the presence of bromide. Evaluation of the antibacterial activity of 30 [7.7]paracyclophanes and related derivatives against selected pathogenic Gram-positive and Gram-negative bacteria exhibited remarkable effects especially against methicillin- and vancomycin-resistant staphylococci and Mycobacterium tuberculosis. For deeper insights into the mechanisms of biosynthesis, the carbamidocyclophane biosynthetic gene cluster in Nostoc sp. CAVN2 was studied. The gene putatively coding for the carbamoyltransferase has been identified. Based on bioinformatic analyses, a possible biosynthetic assembly is discussed.
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biology, Ernst-Moritz-Arndt-University, Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany. michael.preisitsch@uni-greifswald.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Preisitsch
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biotechnology, Ernst-Moritz-Arndt-University, Felix-Hausdorff-Straße 3, 17489 Greifswald, Germany. stefan.heiden@uni-greifswald.de.
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Heiden
authors.affiliation: Leibniz Institute for Molecular Pharmacology (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany. beerbaum@fmp-berlin.de.
authors.forename: Monika
authors.initials: M
authors.lastname: Beerbaum
authors.affiliation: Interfaculty Institute of Microbiology and Infection Medicine, Eberhard Karls University, Auf der Morgenstelle 28, 72076 Tübingen, Germany. timo.niedermeyer@uni-tuebingen.de.|German Centre for Infection Research (DZIF), Partner Site Tübingen (T.H.J.N.) and Partner Site Hannover-Braunschweig, Germany. timo.niedermeyer@uni-tuebingen.de.
authors.forename: Timo H J
authors.initials: TH
authors.lastname: Niedermeyer
authors.affiliation: German Centre for Infection Research (DZIF), Partner Site Tübingen (T.H.J.N.) and Partner Site Hannover-Braunschweig, Germany. schneefeld.marie@mh-hannover.de.|Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. schneefeld.marie@mh-hannover.de.
authors.forename: Marie
authors.initials: M
authors.lastname: Schneefeld
authors.affiliation: German Centre for Infection Research (DZIF), Partner Site Tübingen (T.H.J.N.) and Partner Site Hannover-Braunschweig, Germany. jennifer.herrmann@helmholtz-hzi.de.|Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, and Department of Pharmaceutical Biotechnology, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany. jennifer.herrmann@helmholtz-hzi.de.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Herrmann
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biotechnology, Ernst-Moritz-Arndt-University, Felix-Hausdorff-Straße 3, 17489 Greifswald, Germany. jana.kumpfmueller@leibniz-hki.de.|Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Department of Biomolecular Chemistry, Beutenbergstraße 11a, 07745 Jena, Germany. jana.kumpfmueller@leibniz-hki.de.
authors.forename: Jana
authors.initials: J
authors.lastname: Kumpfmüller
authors.affiliation: Institute of Microbiology and Genetics, Department of Genomic and Applied Microbiology and Göttingen Genomics Laboratory, Georg-August University, Grisebachstraße 8, 37077 Göttingen, Germany. athuerm@gwdg.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Thürmer
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biology, Ernst-Moritz-Arndt-University, Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany. i.neidhardt@tu-braunschweig.de.|Institute of Technology, Department of Pharmacology, Toxicology and Clinical Pharmacy, Technical University of Braunschweig, Mendelssohnstraße 1, 38106 Braunschweig, Germany. i.neidhardt@tu-braunschweig.de.
authors.forename: Inga
authors.initials: I
authors.lastname: Neidhardt
authors.affiliation: Sealife PHARMA GmbH, Technopark 1/Obj.C/EG, 3430 Tulln, Austria. wiesner@sealifepharma.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wiesner
authors.affiliation: Institute of Microbiology and Genetics, Department of Genomic and Applied Microbiology and Göttingen Genomics Laboratory, Georg-August University, Grisebachstraße 8, 37077 Göttingen, Germany. rdaniel@gwdg.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Daniel
authors.affiliation: German Centre for Infection Research (DZIF), Partner Site Tübingen (T.H.J.N.) and Partner Site Hannover-Braunschweig, Germany. rolf.mueller@helmholtz-hzi.de.|Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, and Department of Pharmaceutical Biotechnology, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany. rolf.mueller@helmholtz-hzi.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: German Centre for Infection Research (DZIF), Partner Site Tübingen (T.H.J.N.) and Partner Site Hannover-Braunschweig, Germany. bange.franz@mh-hannover.de.|Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. bange.franz@mh-hannover.de.
authors.forename: Franz-Christoph
authors.initials: FC
authors.lastname: Bange
authors.affiliation: Leibniz Institute for Molecular Pharmacology (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany. schmieder@fmp-berlin.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmieder
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biotechnology, Ernst-Moritz-Arndt-University, Felix-Hausdorff-Straße 3, 17489 Greifswald, Germany. schweder@uni-greifswald.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schweder
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biology, Ernst-Moritz-Arndt-University, Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany. smundt@uni-greifswald.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Mundt
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D003470:Culture Media; D000458:Cyanobacteria / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000378:metabolism*; D005459:Fluorides / Q000494:pharmacology; D006801:Humans; D017680:Potassium Compounds / Q000494:pharmacology; D011193:Potassium Iodide / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D003470:Culture Media; D004988:Ethers, Cyclic; D017680:Potassium Compounds; D011193:Potassium Iodide; C033320:potassium fluoride; D005459:Fluorides
keywords: MRSA; Mycobacterium; Nostoc sp.; [7.7]paracyclophane; bioactivity; biosynthesis; bromo-analogue; carbamidocyclophane; gene cluster; halogen