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Die Suche Nach Neuen Bioaktiven Sekundärmetaboliten Aus Actinomyceten

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Die Suche Nach Neuen Bioaktiven Sekundärmetaboliten Aus Actinomyceten Die Suche nach neuen bioaktiven Sekundärmetaboliten aus Actinomyceten INAUGURALDISSERTATION Zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Albert-Ludwigs-Universität Freiburg im Breisgau vorgelegt von Anja Greule aus Calw 2016 Vorsitzender des Promotionsausschusses: Prof. Dr. Stefan Weber Dekan: Prof. Dr. Manfred Jung Referent: Prof. Dr. Andreas Bechthold Korreferent: Prof. Dr. Oliver Einsle Datum der mündlichen Prüfung: 29. November 2016 In liebevoller Erinnerung an Flo Phantasie ist wichtiger als Wissen, denn Wissen ist begrenzt. Albert Einstein (1879-1955) „Der Dank ist das edle Eingeständnis unserer Grenzen. Wir alle sind aufeinander angewiesen – und dies äußert sich im Geben und Nehmen, im Bitten und Danken.“ (Georg Moser) Nach einer solchen Zeit im Labor kommt man doch mit vielen verschiedenen Menschen in Kontakt und nicht alle Versuche kann man selbst durchführen. Darum möchte ich mich unbedingt bei denen bedanken, die mir direkt oder indirekt bei dieser Arbeit geholfen haben. Zuallererst bedanke ich mich herzlich bei meinem Doktorvater Prof. Dr. Andreas Bechthold für die Möglichkeit meine Dissertation an seinem Lehrstuhl zu machen, der mir diese tollen Themen über- lassen hat, mir aber auch alle Freiheiten gab, in Richtungen zu forschen, die mich am meisten inter- essiert haben. Ich danke meinem Zweitprüfer Prof. Dr. Oliver Einsle für die Übernahme des Koreferats und meinem Drittprüfer Prof. Dr. Stefan Günther. Danke, Prof. Dr. Watanalai und Dr. Bungonsiri Intra von der Mahidol Universität in Bangkok, Thailand. Bungonsiri war sechs Monate mit mir im Labor und wir untersuchten zusammen Actino- kineospora bangkokensis. Nachdem sie zurück in Thailand war durfte ich weiter an unserem Projekt arbeiten. Ein großer Dank gilt Dr. Thomas Paululat der Universität Siegen für die Struktur- aufklärung von Thailandin A und B, sowie von Foxicin A. Danke an Andreas Kulik von der Universität Tübingen für die HPLC-Unterstützung. Vielen Dank an Dr. Stephan Flemming für die tollen Circos-Bilder und die endlosen Telefonate, bis ich endlich zufrieden war…, sowie Hilfe bei Computer-Problemchen. Bezüglich meiner Foxicin-Untersuchungen bedanke ich mich zuerst bei Dr. Iris Peintner für die Ent- deckung von Foxicin A (früher IP1). Dann bedanke ich mich bei Songya Zhang für die Auf- reinigungen von anderen Foxicin-Derivate und NMR-Analysen, herzlichen Dank an Sascha Ferlaino (Pharm. und Med. Chemie) für die vielen NMR-Vermessungen sowie Marija Marolt und Dr. Steffen Lüdeke für die VCD- und IR-Messungen. Ein Dankeschön gilt auch Dr. Claudia Jessen-Trefzer. Während den Untersuchungen der Foxicin-Aktivität musste ich verschiedene Versuche in unter- schiedlichen Laboren durchführen – danke an alle! Der Hemmhoftest der Cyanobakterien bei Dr. Ekaterina Kuchmina, AG Wilde (Biologie), der Atmungskettenversuch bei Sabrina Burschel der AG Friedrich (Biochemie), der MTA Assay sowie das in silico Docking mit Cytbc1 wurde von Christian de Ford von der AG Merfort (Pharm. Biologie und Biotechnologie) durchgeführt. Foxicin A wurde von Dr. Matthias Rottmann von der AG Bruns (Swiss Tropical and Public Health Institute, Basel, Schweiz) gegen Plasmodium falciparum getestet. Daniel Álvarez von der AG Beyer (Biologie) testete Foxicin gegen Arabidopsis thaliana. Ich danke Denise Deubel, dass sie mein Thema weiterführt! Bei dem Versuch der heterologen Expression des Foxicin-Genclusters danke ich Prof. Dr. Francis Stewart, TU Dresden für die rekombinations-freudigen E. coli-Stämme, der pCAP01-Vektor wurde von Prof. Dr. Bradley Moore vom Scripps Institution of Oceanography, Universität von San Diego zu Verfügung gestellt, sowie von Dr. Vladimir Larionov der Hefestamm S. cerevisiae VL6-48N für die TAR-Klonierung. Ich danke Prof. Dr. Max Cryle für die tolle Diskussion über A-Domänen, das Zukommenlassen des Protokol zum in vitro Assay und die Möglichkeit nun in seinem Labor am anderen Ende der Welt meine Postdoc-Zeit zu verbringen. Für die Unterstützung bei allen Fragen zur Aufreinigung von Sekundärmetaboliten und sonstigen Problemen tausend Dank an die gute Seele der Arbeitsgruppe - Elisabeth Welle - und sonstigen Dingen danke an Marcus Essing, sowie Sandra Groß, Sandra Cabrera und Tanja Herbstritt. Für die tolle Atmosphäre im Arbeitskreis, beim Mittagessen, in den Kuchenzeiten und sonstigem netten Gespräch – schön war‘s: Irene Santillana, Suzan Samra, Denise Deubel, Yvonne Schmidt- Bohli, Philipp Schwarzer, Olya Tsypik, Roman Makitrynskyy, Astrid Erber, Stefanie Hackl, Julia Wunsch-Palasis, Tanja Heitzler, Jasmin Kröger, Songya Zhang, Jing Zhu, ChiJian Zuo, Miaomiao Li, sowie der AG Merfort! Ein herzliches Dankschön auch Dr. Gabriele Weitnauer! Ich danke auch meinen vielen Studenten, die mir während meiner Zeit hier zur Seite gestellt wurden, ob Wahlpflichtpraktikant, Bachelor, Master oder Diplom: Vor allem aber Marcel Rommel, Linda Zambolin, und auch vielen anderen, die nicht direkt mit mir arbeiteten, aber mit ihnen eine tolle Zeit hatte: Maxie Schmitt, Jannis Brehm, Veronika Brinschwitz, Nils Gummerlich, Fabienne Gut- acker und Michael Keppler. Danke den fleißigen Korrekturlesern: Denise Deubel, Philipp Schwarzer, Yvonne Schmidt-Bohli, Tina Strobel, Suzan Samra, Stephan Flemming Anton Ippendorf und . Zum Schluss möchte ich mich noch einmal speziell bei meinen einzigartigen Freunden bedanken: Irene Santillana - allerliebste Guapa - meine andere „Orangen-Hälfte“… ich habe unsere gemeinsame Zeit in 01018 so sehr genossen! Danke für alle Gespräche innerhalb und außerhalb des Labors, deine positive Art, dem Unterschlupf, … und dass du immer für mich da warst! Tina Strobel - die leider erst nach ihrer Laborzeit eine teure Freundin geworden ist. Danke für die Frauenabende, den Kochsessions, dem Feiern und faul auf dem Sofa liegen, dem kommenden Urlaub und so vieles mehr… Stephan Flemming - es ist auch mir eine große Freude! =) Suzan Samra – für mich bist du einer der tollsten und stärksten Menschen, die ich kenne! Danke für die gemeinsame (Labor)Zeit, die „Oh nein“- und „Aussteigen“-Momente mit Leo, das leckere Essen und und und… Wir sehen uns wieder in unserer Heimat! … danke, dass es euch gibt!!! Daniel – danke, du hast mir geholfen, meinen Weg zu finden. Zu guter Letzt danke ich natürlich meiner Familie: Meinen Eltern Claudia und Alfred, meinen Brüdern Michael und Peter sowie meinen Großeltern und dem restlichen Greule-Klan. Publikationen Medema M.H., Kottmann R., Yilmaz P., Cummings M., Biggins J.B., Blin K., Bruijn I. de, Chooi Y.H., Claesen J., Coates R.C., Cruz-Morales P., Duddela S., Düsterhus S., Edwards D.J., Fewer D.P., Garg N., Geiger C., Gomez-Escribano J.P., Greule A., Hadjithomas M., Haines A.S., Helfrich E.J.N., Hillwig M.L., Ishida K., Jones A.C., Jones C.S., Jungmann K., Kegler C., Kim H.U., Kötter P., Krug D., Masschelein J., Melnik A.V., Mantovani S.M., Monroe E.A., Moore M., Moss N., Nützmann H.- W., Pan G., Pati A., Petras D., Reen F.J., Rosconi F., Rui Z., Tian Z., Tobias N.J., Tsunematsu Y., Wiemann P., Wyckoff E., Yan X., Yim G., Yu F., Xie Y., Aigle B., Apel A.K., Balibar C.J., Balskus E.P., Barona-Gómez F., Bechthold A., Bode H.B., Borriss R., Brady S.F., Brakhage A.A., Caffrey P., Cheng Y.-Q., Clardy J., Cox R.J., Mot R. de, Donadio S., Donia M.S., van der Donk W.A., Dorrestein P.C., Doyle S., Driessen A.J.M., Ehling-Schulz M., Entian K.-D., Fischbach M.A., Gerwick L., Gerwick W.H., Gross H., Gust B., Hertweck C., Höfte M., Jensen S.E., Ju J., Katz L., Kaysser L., Klassen J.L., Keller N.P., Kormanec J., Kuipers O.P., Kuzuyama T., Kyrpides N.C., Kwon H.-J., Lautru S., Lavigne R., Lee C.Y., Linquan B., Liu X., Liu W., Luzhetskyy A., Mahmud T., Mast Y., Méndez C., Metsä-Ketelä M., Micklefield J., Mitchell D.A., Moore B.S., Moreira L.M., Müller R., Neilan B.A., Nett M., Nielsen J., O'Gara F., Oikawa H., Osbourn A., Osburne M.S., Ostash B., Payne S.M., Pernodet J.-L., Petricek M., Piel J., Ploux O., Raaijmakers J.M., Salas J.A., Schmitt E.K., Scott B., Seipke R.F., Shen B., Sherman D.H., Sivonen K., Smanski M.J., Sosio M., Stegmann E., Süssmuth R.D., Tahlan K., Thomas C.M., Tang Y., Truman A.W., Viaud M., Walton J.D., Walsh C.T., Weber T., van Wezel G.P., Wilkinson B., Willey J.M., Wohlleben W., Wright G.D., Ziemert N., Zhang C., Zotchev S.B., Breitling R., Takano E. & Glöckner F.O., (2015), Minimum Information about a Biosynthetic Gene Cluster, Nat Chem Biol 11: 625–631. Intra B., Greule A., Bechthold A., Euanorasetr J., Paululat T. & Panbangred W., (2016), Thailandins A and B, the New Pentaene Polyene Compounds with Antifungal Activity against Anthracnose Fungi and Pathogenic Yeasts produced by Actinokineospora bangkokensis strain 44EHWT, J. Agric. Food Chem., 64 (25): 5171–5179. Greule A., Zhang S., Paululat T. & Bechthold A., (2016), From a Natural Product to its Biosynthetic Gene Cluster: A Demonstration using Polyketomycin from Streptomyces diastato- chromogenes Tü6028, J Vis Exp. (), e54952, Video unter http://www.jove.com/video/54952. Greule A., Peintner I., Zhang S., Marolt M., Jessen-Trefzer C., Deubel D., De Ford C., Burschel S., Li S.-M., Friedrich T., Merfort I., Lüdeke S., Bisel P., Müller M., Paululat T. & Bechthold A., (2016), The Foxicin Biosynthesis Gene Cluster: widely distributed – but silent, eingereicht. Greule A., Intra B., Flemming S., Rommel M., Panbangred W. & Bechthold A., (2016), The Draft Genome Sequence of Actinokineospora bangkokensis 44EHWT reveals the biosynthetic pathway of Antifungal Compound Thailandins with Unusual Extender Unit Butylmalonyl-CoA, eingereicht. Greule A., Flemming S.
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