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1. Investigation of bacterial secondary metabolite pathways from Sorangium cellulosum

Author

Jungmann, Katrin and Müller, Rolf

Subjects
Sekundärmetabolite, Biosynthese, natural products, secondary metabolites, Naturstoff, antibiotics, Myxobakterien, myxobacteria, ddc:500, ddc:620, Antibiotikum, biosynthesis, Sekundärmetabolit
Abstract

Natural products have always been an important source for new lead structures especially in the context of increasing resistance rates against contemporarily available antibiotics. In search of new antiinfectives it has proven to be advantageous to explore the secondary metabolome of yet unknown microorganisms and microoragnisms from ecological niches such as myxobacteria. Myxobacteria, soil-dwelling Gram-negative δ-proteobacteria, have repeatedly demonstrated their enormous potential as prolific produces of structurally diverse secondary metabolites in the last decades. Chlorotonil A, produced by the myxobacterium Sorangium cellulosum So ce 1525, apart from its structural peculiarities shows highly promising bioactivity against the problematic malaria pathogen Plasmodium falciparum. The biosynthesis of Chlorotonil A was elucidated whereas a comparison with the biosynthetic pathway of the related streptomycete metabolite anthracimycin allowed for insights into the underlying biosynthetic processes in greater depth. Moreover the chlorotonil biosynthetic gene cluster was successfully mobilized from So ce1525 and subsequently adapted for establishment of a platform for hetrologous expression. Using a semi-synthetic route, also first natural product derivatives, which are giving direction for further studies towards semi-synthesis of chlorotonil derivatives with enhanced pharmacokinetic properties, were generated. In addition, the biosynthesis of the two secondary metabolites maracen and maracin, produced by several Sorangium species and exhibting auspicious anti-tuberculosis activity, was investigated. In derogation of the classical approach, methods of synthetic biology were used to generate an artificial gene cluster based on the working hypothesis. The work accomplished paves the way for extended analysis of the biosynthetic processes and at the same time enables the installation of a system for heterologous expression of the pathway. Naturstoffe sind seit jeher eine bedeutende Quelle auf der Suche nach neuen Leitstrukturen, insbesondere vor dem Hintergrund der sich verschärfenden Resistenzentwicklung gegen Antibiotika. Dabei hat es sich bewährt, bisher unerforschte Lebensräume und Mikroorganismen – wie beispielsweise Myxobakterien zu untersuchen. Myxobakterien – ubiquitär vorkommende Gram-negative δ-Proteobakterien - haben in den letzten Jahrzehnten ihre enorme Kapazität zur Produktion strukturell diverser Sekundärmetabolite unter Beweis gestellt. Aus dem Myxobakterium Sorangium cellulosum So ce1525 stammt der neuartige Sekundärmetabolit Chlorotonil A, der neben seinen strukturellen Besonderheiten auch sehr vielversprechende Bioaktivität, insbesondere gegen den problematischen Malariaerreger Plasmodium falciparum aufweist. Die Biosynthese dieses Sekundärmetaboliten konnte im Rahmen dieser Dissertation aufgeklärt werden. Zudem erlaubte ein Vergleich mit dem Biosyntheseweg des strukturell ähnlichen Streptomyceten-Sekundärmetaboliten Anthracimycin tiefergehende Einblicke in die zugrundeliegenden Biosyntheseprozesse. Weiterhin konnte der Chlorotonil Biosynthesegencluster mobilisiert und für die Etablierung einer Plattform zur heterologen Expression adaptiert werden. Darüber hinaus wurden auf semi-synthetischem Weg erste Derivate des Naturstoffes erzeugt, die wegweisend für erweiterte Studien mit dem Ziel der Herstellung bioaktiver Chlorotonil-Derivate mit verbesserten pharmakokinetischen Eigenschaften. Außerdem wurde die Biosynthese der beiden Sekundärmetabolite Maracen und Maracen, die ebenfalls von Vertretern der Gattung Sorangium produziert werden und vielversprechende Wirkung gegen Tuberkuloseerreger zeigen, untersucht. Anders als im klassischen Ansatz wurde hierbei mit Methoden der synthetischen Biologie ein artifizieller Gencluster anhand der Arbeitshypothese – Maracen/Maracin Biosynthese durch stufenweise enzymatische Unmwandlung von Eicosapentaensäure - erzeugt. Die durchgeführten Arbeiten ebnen den Weg für Untersuchungen der biosynthetischen Abläufe und ermöglichen gleichzeitig die Etablierung der heterologen Expression des Genclusters.

Published
2016
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2. Minimum Information about a Biosynthetic Gene cluster: commentary

Author

Medema, Marnix H, Kottmann, Renzo, Yilmaz, Pelin, Cummings, Matthew, Biggins, John B, Blin, Kai, de Bruijn, Irene, Chooi, Yit Heng, Claesen, Jan, Coates, R Cameron, Cruz-Morales, Pablo, Duddela, Srikanth, Dusterhus, Stephanie, Edwards, Daniel J, Fewer, David P, Garg, Neha, Geiger, Christoph, Gomez-Escribano, Juan Pablo, Greule, Anja, Hadjithomas, Michalis, Haines, Anthony S, Helfrich, Eric J N, Hillwig, Matthew L, Ishida, Keishi, Jones, Adam C, Jones, Carla S, Jungmann, Katrin, Kegler, Carsten, Kim, Hyun Uk, Kotter, Peter, Krug, Daniel, Masschelein, Joleen, Melnik, Alexey V, Mantovani, Simone M, Monroe, Emily A, Moore, Marcus, Moss, Nathan, Nutzmann, Hans-Wilhelm, Pan, Guohui, Pati, Amrita, Petras, Daniel, Reen, F Jerry, Rosconi, Federico, Rui, Zhe, Tian, Zhenhua, Tobias, Nicholas J, Tsunematsu, Yuta, Wiemann, Philipp, Wyckoff, Elizabeth, Yan, Xiaohui, Yim, Grace, Yu, Fengan, Xie, Yunchang, Aigle, Bertrand, Apel, Alexander K, Balibar, Carl J, Balskus, Emily P, Barona-Gomez, Francisco, Bechthold, Andreas, Bode, Helge B, Borriss, Rainer, Brady, Sean F, Brakhage, Axel A, Caffrey, Patrick, Cheng, Yi-Qiang, Clardy, Jon, Cox, Russell J, De Mot, Rene, Donadio, Stefano, Donia, Mohamed S, van der Donk, Wilfred A, Dorrestein, Pieter C, Doyle, Sean, Driessen, Arnold J M, Ehling-Schulz, Monika, Entian, Karl-Dieter, Fischbach, Michael A, Gerwick, Lena, Gerwick, William H, Gross, Harald, Gust, Bertolt, Hertweck, Christian, Hofte, Monica, Jensen, Susan E, Ju, Jianhua, Katz, Leonard, Kaysser, Leonard, Klassen, Jonathan L, Keller, Nancy P, Kormanec, Jan, Kuipers, Oscar P, Kuzuyama, Tomohisa, Kyrpides, Nikos C, Kwon, Hyung-Jin, Lautru, Sylvie, Lavigne, Rob, Lee, Chia Y, Linquan, Bai, Liu, Xinyu, Liu, Wen, Luzhetskyy, Andriy, Mahmud, Taifo, Mast, Yvonne, Mendez, Carmen, Metsa-Ketela, Mikko, Micklefield, Jason, Mitchell, Douglas A, Moore, Bradley S, Moreira, Leonilde M, Muller, Rolf, Neilan, Brett A, Nett, Markus, Nielsen, Jens, O'Gara, Fergal, Oikawa, Hideaki, Osbourn, Anne, Osburne, Marcia S, Ostash, Bohdan, Payne, Shelley M, Pernodet, Jean-Luc, Petricek, Miroslav, Piel, Jorn, Ploux, Olivier, Raaijmakers, Jos M, Salas, Jose A, Schmitt, Esther K, Scott, Barry, Seipke, Ryan F, Shen, Ben, Sherman, David H, Sivonen, Kaarina, Smanski, Michael J, Sosio, Margherita, Stegmann, Evi, Sussmuth, Roderich D, Tahlan, Kapil, Thomas, Christopher M, Tang, Yi, Truman, Andrew W, Viaud, Muriel, Walton, Jonathan D, Walsh, Christopher T, Weber, Tilmann, van Wezel, Gilles P, Wilkinson, Barrie, Willey, Joanne M, Wohlleben, Wolfgang, Wright, Gerard D, Ziemert, Nadine, Zhang, Changsheng, Zotchev, Sergey B, Breitling, Rainer, Takano, Eriko, Glockner, Frank Oliver, and Microbial Ecology (ME)

Subjects
international
Abstract

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.

Published
2015

3. Minimum information about a biosynthetic gene cluster

Author

Medema, Marnix H., Kottmann, Renzo, Yilmaz, Pelin, Cummings, Matthew, Biggins, John B., Kai, Blin, de Bruijn, Irene, Chooi, Yit Heng, Claesen, Jan, Coates, R. Cameron, Cruz-Morales, Pablo, Duddela, Srikanth, Düsterhus, Stephanie, Edwards, Daniel J., Fewer, David P., Garg, Neha, Geiger, Christoph, Gomez-Escribano, Juan Pablo, Greule, Anja, Hadjithomas, Michalis, Haines, Anthony S., Helfrich, Eric J. N., Hillwig, Matthew L., Ishida, Keishi, Jones, Adam C., Jones, Carla S., Jungmann, Katrin, Kegler, Carsten, Kim, Hyun Uk, Kötter, Peter, Krug, Daniel, Masschelein, Joleen, Melnik, Alexey V., Mantovan, Simone M., Monroe, Emily A., Moore, Marcus, Moss, Nathan, Nützmann, Hans-Wilhelm, Pan, Guohui, Pati, Amrita, Petras, Daniel, Reen, F. Jerry, Rosconi, Federico, Rui, Zhe, Tian, Zhenhua, Tobias, Nicholas J., Tsunematsu, Yuta, Wiemann, Philipp, Wyckoff, Elizabeth, Yan, Xiaohui, Yim, Grace, Yu, Fengan, Xie, Yunchang, Aigle, Bertrand, Apel, Alexander K., Balibar, Carl J., Balskus, Emily P., Barona-Gómez, Francisco, Bechthold, Andreas, Bode, Helge Björn, Borriss, Rainer, Brady, Sean F., Brakhage, Axel A., Caffrey, Patrick, Cheng, Yi-Qiang, Clardy, Jon, Cox, Russell J., De Mot, René, Donadio, Stefano, Donia, Mohamed S., van der Donk, Wilfred A., Dorrestein, Pieter C., Doyle, Sean, Driessen, Arnold J. M., Ehling-Schulz, Monika, Entian, Karl-Dieter, Fischbach, Michael A., Gerwick, Lena, Gerwick, William H., Gross, Harald, Gust, Bertolt, Hertweck, Christian, Höfte, Monica, Jensen, Susan E., Ju, Jianhua, Katz, Leonard, Kaysser, Leonard, Klassen, Jonathan L., Keller, Nancy P., Kormanec, Jan, Kuipers, Oscar P., Kuzuyama, Tomohisa, Kyrpides, Nikos C., Kwon, Hyung-Jin, Lautru, Sylvie, Lavigne, Rob, Lee, Chia Y., Linquan, Bai, Liu, Xinyu, Liu, Wen, Luzhetskyy, Andriy, Mahmud, Taifo, Mast, Yvonne, Méndez, Carmen, Metsä-Ketelä, Mikko, Micklefield, Jason, Mitchell, Douglas A., Moore, Bradley S., Moreira, Leonilde M., Müller, Rolf, Neilan, Brett A., Nett, Markus, Nielsen, Jens, O’Gara, Fergal, Oikawa, Hideaki, Osbourn, Anne, Osburne, Marcia S., Ostash, Bohdan, Payne, Shelley M., Pernodet, Jean-Luc, Petricek, Miroslav, Piel, Jörn, Ploux, Olivier, Raaijmakers, Jos M., Salas, José A., Schmitt, Esther K., Scott, Barry, Seipke, Ryan F., Shen, Ben, Sherman, David H., Sivonen, Kaarina, Smanski, Michael J., Sosio, Margherita, Stegmann, Evi, Süssmuth, Roderich D., Tahlan, Kapil, Thomas, Christopher M., Tang, Yi, Truman, Andrew W., Viaud, Muriel, Walton, Jonathan D., Walsh, Christopher T., Weber, Tilmann, van Wezel, Gilles P., Wilkinson, Barrie, Willey, Joanne M., Wohlleben, Wolfgang, Wright, Gerard D., Ziemert, Nadine, Zhang, Changsheng, Zotchev, Sergey B., Breitling, Rainer, Takano, Eriko, Glöckner, Frank Oliver, Medema, Marnix H., Kottmann, Renzo, Yilmaz, Pelin, Cummings, Matthew, Biggins, John B., Kai, Blin, de Bruijn, Irene, Chooi, Yit Heng, Claesen, Jan, Coates, R. Cameron, Cruz-Morales, Pablo, Duddela, Srikanth, Düsterhus, Stephanie, Edwards, Daniel J., Fewer, David P., Garg, Neha, Geiger, Christoph, Gomez-Escribano, Juan Pablo, Greule, Anja, Hadjithomas, Michalis, Haines, Anthony S., Helfrich, Eric J. N., Hillwig, Matthew L., Ishida, Keishi, Jones, Adam C., Jones, Carla S., Jungmann, Katrin, Kegler, Carsten, Kim, Hyun Uk, Kötter, Peter, Krug, Daniel, Masschelein, Joleen, Melnik, Alexey V., Mantovan, Simone M., Monroe, Emily A., Moore, Marcus, Moss, Nathan, Nützmann, Hans-Wilhelm, Pan, Guohui, Pati, Amrita, Petras, Daniel, Reen, F. Jerry, Rosconi, Federico, Rui, Zhe, Tian, Zhenhua, Tobias, Nicholas J., Tsunematsu, Yuta, Wiemann, Philipp, Wyckoff, Elizabeth, Yan, Xiaohui, Yim, Grace, Yu, Fengan, Xie, Yunchang, Aigle, Bertrand, Apel, Alexander K., Balibar, Carl J., Balskus, Emily P., Barona-Gómez, Francisco, Bechthold, Andreas, Bode, Helge Björn, Borriss, Rainer, Brady, Sean F., Brakhage, Axel A., Caffrey, Patrick, Cheng, Yi-Qiang, Clardy, Jon, Cox, Russell J., De Mot, René, Donadio, Stefano, Donia, Mohamed S., van der Donk, Wilfred A., Dorrestein, Pieter C., Doyle, Sean, Driessen, Arnold J. M., Ehling-Schulz, Monika, Entian, Karl-Dieter, Fischbach, Michael A., Gerwick, Lena, Gerwick, William H., Gross, Harald, Gust, Bertolt, Hertweck, Christian, Höfte, Monica, Jensen, Susan E., Ju, Jianhua, Katz, Leonard, Kaysser, Leonard, Klassen, Jonathan L., Keller, Nancy P., Kormanec, Jan, Kuipers, Oscar P., Kuzuyama, Tomohisa, Kyrpides, Nikos C., Kwon, Hyung-Jin, Lautru, Sylvie, Lavigne, Rob, Lee, Chia Y., Linquan, Bai, Liu, Xinyu, Liu, Wen, Luzhetskyy, Andriy, Mahmud, Taifo, Mast, Yvonne, Méndez, Carmen, Metsä-Ketelä, Mikko, Micklefield, Jason, Mitchell, Douglas A., Moore, Bradley S., Moreira, Leonilde M., Müller, Rolf, Neilan, Brett A., Nett, Markus, Nielsen, Jens, O’Gara, Fergal, Oikawa, Hideaki, Osbourn, Anne, Osburne, Marcia S., Ostash, Bohdan, Payne, Shelley M., Pernodet, Jean-Luc, Petricek, Miroslav, Piel, Jörn, Ploux, Olivier, Raaijmakers, Jos M., Salas, José A., Schmitt, Esther K., Scott, Barry, Seipke, Ryan F., Shen, Ben, Sherman, David H., Sivonen, Kaarina, Smanski, Michael J., Sosio, Margherita, Stegmann, Evi, Süssmuth, Roderich D., Tahlan, Kapil, Thomas, Christopher M., Tang, Yi, Truman, Andrew W., Viaud, Muriel, Walton, Jonathan D., Walsh, Christopher T., Weber, Tilmann, van Wezel, Gilles P., Wilkinson, Barrie, Willey, Joanne M., Wohlleben, Wolfgang, Wright, Gerard D., Ziemert, Nadine, Zhang, Changsheng, Zotchev, Sergey B., Breitling, Rainer, Takano, Eriko, and Glöckner, Frank Oliver

Abstract

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.

Published
2015

4. Minimum Information about a Biosynthetic Gene cluster

Author

Medema, M.H., Kottmann, Renzo, Yilmaz, Pelin, Cummings, Matthew, Biggins, J.B., Blin, Kai, De Bruijn, Irene, Chooi, Yit Heng, Claesen, Jan, Coates, R.C., Cruz-Morales, Pablo, Duddela, Srikanth, Düsterhus, Stephanie, Edwards, Daniel J., Fewer, David P., Garg, Neha, Geiger, Christoph, Gomez-Escribano, Juan Pablo, Greule, Anja, Hadjithomas, Michalis, Haines, Anthony S., Helfrich, Eric J.N., Hillwig, Matthew L., Ishida, Keishi, Jones, Adam C., Jones, Carla S., Jungmann, Katrin, Kegler, Carsten, Kim, Hyun Uk, Kötter, Peter, Krug, Daniel, Masschelein, Joleen, Melnik, Alexey V., Mantovani, Simone M., Monroe, Emily A., Moore, Marcus, Moss, Nathan, Nützmann, Hans Wilhelm, Pan, Guohui, Pati, Amrita, Petras, Daniel, Reen, F.J., Rosconi, Federico, Rui, Zhe, Tian, Zhenhua, Tobias, Nicholas J., Tsunematsu, Yuta, Wiemann, Philipp, Wyckoff, Elizabeth, Yan, Xiaohui, Yim, Grace, Yu, Fengan, Xie, Yunchang, Aigle, Bertrand, Apel, Alexander K., Balibar, Carl J., Balskus, Emily P., Barona-Gómez, Francisco, Bechthold, Andreas, Bode, Helge B., Borriss, Rainer, Brady, Sean F., Brakhage, Axel A., Caffrey, Patrick, Cheng, Yi Qiang, Clardy, Jon, Cox, Russell J., De Mot, René, Donadio, Stefano, Donia, Mohamed S., Van Der Donk, Wilfred A., Dorrestein, Pieter C., Doyle, Sean, Driessen, Arnold J.M., Ehling-Schulz, Monika, Entian, Karl Dieter, Fischbach, Michael A., Gerwick, Lena, Gerwick, William H., Gross, Harald, Gust, Bertolt, Hertweck, Christian, Höfte, Monica, Jensen, Susan E., Ju, Jianhua, Katz, Leonard, Kaysser, Leonard, Klassen, Jonathan L., Keller, Nancy P., Kormanec, Jan, Kuipers, Oscar P., Kuzuyama, Tomohisa, Kyrpides, Nikos C., Kwon, Hyung Jin, Lautru, Sylvie, Lavigne, Rob, Lee, Chia Y., Linquan, Bai, Liu, Xinyu, Liu, Wen, Luzhetskyy, Andriy, Mahmud, Taifo, Mast, Yvonne, Méndez, Carmen, Metsä-Ketelä, Mikko, Micklefield, Jason, Mitchell, Douglas A., Moore, Bradley S., Moreira, Leonilde M., Müller, Rolf, Neilan, Brett A., Nett, Markus, Nielsen, Jens, O'Gara, Fergal, Oikawa, Hideaki, Osbourn, Anne, Osburne, Marcia S., Ostash, Bohdan, Payne, Shelley M., Pernodet, Jean Luc, Petricek, Miroslav, Piel, Jörn, Ploux, Olivier, Raaijmakers, Jos M., Salas, José A., Schmitt, Esther K., Scott, Barry, Seipke, Ryan F., Shen, Ben, Sherman, David H., Sivonen, Kaarina, Smanski, Michael J., Sosio, Margherita, Stegmann, Evi, Süssmuth, Roderich D., Tahlan, Kapil, Thomas, Christopher M., Tang, Yi, Truman, Andrew W., Viaud, Muriel, Walton, Jonathan D., Walsh, Christopher T., Weber, Tilmann, Van Wezel, Gilles P., Wilkinson, Barrie, Willey, Joanne M., Wohlleben, Wolfgang, Wright, Gerard D., Ziemert, Nadine, Zhang, Changsheng, Zotchev, Sergey B., Breitling, Rainer, Takano, Eriko, Glöckner, Frank Oliver, Medema, M.H., Kottmann, Renzo, Yilmaz, Pelin, Cummings, Matthew, Biggins, J.B., Blin, Kai, De Bruijn, Irene, Chooi, Yit Heng, Claesen, Jan, Coates, R.C., Cruz-Morales, Pablo, Duddela, Srikanth, Düsterhus, Stephanie, Edwards, Daniel J., Fewer, David P., Garg, Neha, Geiger, Christoph, Gomez-Escribano, Juan Pablo, Greule, Anja, Hadjithomas, Michalis, Haines, Anthony S., Helfrich, Eric J.N., Hillwig, Matthew L., Ishida, Keishi, Jones, Adam C., Jones, Carla S., Jungmann, Katrin, Kegler, Carsten, Kim, Hyun Uk, Kötter, Peter, Krug, Daniel, Masschelein, Joleen, Melnik, Alexey V., Mantovani, Simone M., Monroe, Emily A., Moore, Marcus, Moss, Nathan, Nützmann, Hans Wilhelm, Pan, Guohui, Pati, Amrita, Petras, Daniel, Reen, F.J., Rosconi, Federico, Rui, Zhe, Tian, Zhenhua, Tobias, Nicholas J., Tsunematsu, Yuta, Wiemann, Philipp, Wyckoff, Elizabeth, Yan, Xiaohui, Yim, Grace, Yu, Fengan, Xie, Yunchang, Aigle, Bertrand, Apel, Alexander K., Balibar, Carl J., Balskus, Emily P., Barona-Gómez, Francisco, Bechthold, Andreas, Bode, Helge B., Borriss, Rainer, Brady, Sean F., Brakhage, Axel A., Caffrey, Patrick, Cheng, Yi Qiang, Clardy, Jon, Cox, Russell J., De Mot, René, Donadio, Stefano, Donia, Mohamed S., Van Der Donk, Wilfred A., Dorrestein, Pieter C., Doyle, Sean, Driessen, Arnold J.M., Ehling-Schulz, Monika, Entian, Karl Dieter, Fischbach, Michael A., Gerwick, Lena, Gerwick, William H., Gross, Harald, Gust, Bertolt, Hertweck, Christian, Höfte, Monica, Jensen, Susan E., Ju, Jianhua, Katz, Leonard, Kaysser, Leonard, Klassen, Jonathan L., Keller, Nancy P., Kormanec, Jan, Kuipers, Oscar P., Kuzuyama, Tomohisa, Kyrpides, Nikos C., Kwon, Hyung Jin, Lautru, Sylvie, Lavigne, Rob, Lee, Chia Y., Linquan, Bai, Liu, Xinyu, Liu, Wen, Luzhetskyy, Andriy, Mahmud, Taifo, Mast, Yvonne, Méndez, Carmen, Metsä-Ketelä, Mikko, Micklefield, Jason, Mitchell, Douglas A., Moore, Bradley S., Moreira, Leonilde M., Müller, Rolf, Neilan, Brett A., Nett, Markus, Nielsen, Jens, O'Gara, Fergal, Oikawa, Hideaki, Osbourn, Anne, Osburne, Marcia S., Ostash, Bohdan, Payne, Shelley M., Pernodet, Jean Luc, Petricek, Miroslav, Piel, Jörn, Ploux, Olivier, Raaijmakers, Jos M., Salas, José A., Schmitt, Esther K., Scott, Barry, Seipke, Ryan F., Shen, Ben, Sherman, David H., Sivonen, Kaarina, Smanski, Michael J., Sosio, Margherita, Stegmann, Evi, Süssmuth, Roderich D., Tahlan, Kapil, Thomas, Christopher M., Tang, Yi, Truman, Andrew W., Viaud, Muriel, Walton, Jonathan D., Walsh, Christopher T., Weber, Tilmann, Van Wezel, Gilles P., Wilkinson, Barrie, Willey, Joanne M., Wohlleben, Wolfgang, Wright, Gerard D., Ziemert, Nadine, Zhang, Changsheng, Zotchev, Sergey B., Breitling, Rainer, Takano, Eriko, and Glöckner, Frank Oliver

Abstract

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.

Published
2015

6. Two of a KindThe Biosynthetic Pathways of Chlorotonil and Anthracimycin

Author

Jungmann, Katrin, Jansen, Rolf, Gerth, Klaus, Huch, Volker, Krug, Daniel, Fenical, William, and Müller, Rolf

Abstract

Chlorotonil A is a novel polyketide isolated from the myxobacterium Sorangium cellulosumSo ce1525 that features a unique gem-dichloro-1,3-dione moiety. It exhibits potent bioactivity, most notably against the problematic malaria pathogen Plasmodium falciparumin the nanomolar range. In addition, strong antibacterial and moderate antifungal activity were determined. The outstanding biological activity of chlorotonil A as well as its unusual chemical structure triggered our interest in elucidating its biosynthesis, a prerequisite for alteration of the scaffold by synthetic biology approaches. This endeavor was facilitated by a recent report describing the strikingly similar structure of anthracimycin from a marine streptomycete, a compound of considerable interest due to its potent antibacterial activity. In this study, we report the identification and characterization of the chlorotonil A biosynthetic gene cluster from So ce1525 and compare it with that for anthracimycin biosynthesis. Access to both gene clusters allowed us to highlight commonalities between the two pathways and revealed striking differences, some of which can plausibly explain the structural differences observed between these intriguing natural products.

Published
2015
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7. Investigation of bacterial secondary metabolite pathways from Sorangium cellulosum

Author

Jungmann, Katrin

Abstract

Natural products have always been an important source for new lead structures especially in the context of increasing resistance rates against contemporarily available antibiotics. In search of new antiinfectives it has proven to be advantageous to explore the secondary metabolome of yet unknown microorganisms and microoragnisms from ecological niches such as myxobacteria. Myxobacteria, soil-dwelling Gram-negative δ-proteobacteria, have repeatedly demonstrated their enormous potential as prolific produces of structurally diverse secondary metabolites in the last decades. Chlorotonil A, produced by the myxobacterium Sorangium cellulosum So ce 1525, apart from its structural peculiarities shows highly promising bioactivity against the problematic malaria pathogen Plasmodium falciparum. The biosynthesis of Chlorotonil A was elucidated whereas a comparison with the biosynthetic pathway of the related streptomycete metabolite anthracimycin allowed for insights into the underlying biosynthetic processes in greater depth. Moreover the chlorotonil biosynthetic gene cluster was successfully mobilized from So ce1525 and subsequently adapted for establishment of a platform for hetrologous expression. Using a semi-synthetic route, also first natural product derivatives, which are giving direction for further studies towards semi-synthesis of chlorotonil derivatives with enhanced pharmacokinetic properties, were generated. In addition, the biosynthesis of the two secondary metabolites maracen and maracin, produced by several Sorangium species and exhibting auspicious anti-tuberculosis activity, was investigated. In derogation of the classical approach, methods of synthetic biology were used to generate an artificial gene cluster based on the working hypothesis. The work accomplished paves the way for extended analysis of the biosynthetic processes and at the same time enables the installation of a system for heterologous expression of the pathway.

Published
2015

8. Minimum Information about a Biosynthetic Gene cluster.

Author

Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, de Bruijn I, Chooi YH, Claesen J, Coates RC, Cruz-Morales P, Duddela S, Düsterhus S, Edwards DJ, Fewer DP, Garg N, Geiger C, Gomez-Escribano JP, Greule A, Hadjithomas M, Haines AS, Helfrich EJ, Hillwig ML, Ishida K, Jones AC, Jones CS, Jungmann K, Kegler C, Kim HU, Kötter P, Krug D, Masschelein J, Melnik AV, Mantovani SM, Monroe EA, Moore M, Moss N, Nützmann HW, Pan G, Pati A, Petras D, Reen FJ, Rosconi F, Rui Z, Tian Z, Tobias NJ, Tsunematsu Y, Wiemann P, Wyckoff E, Yan X, Yim G, Yu F, Xie Y, Aigle B, Apel AK, Balibar CJ, Balskus EP, Barona-Gómez F, Bechthold A, Bode HB, Borriss R, Brady SF, Brakhage AA, Caffrey P, Cheng YQ, Clardy J, Cox RJ, De Mot R, Donadio S, Donia MS, van der Donk WA, Dorrestein PC, Doyle S, Driessen AJ, Ehling-Schulz M, Entian KD, Fischbach MA, Gerwick L, Gerwick WH, Gross H, Gust B, Hertweck C, Höfte M, Jensen SE, Ju J, Katz L, Kaysser L, Klassen JL, Keller NP, Kormanec J, Kuipers OP, Kuzuyama T, Kyrpides NC, Kwon HJ, Lautru S, Lavigne R, Lee CY, Linquan B, Liu X, Liu W, Luzhetskyy A, Mahmud T, Mast Y, Méndez C, Metsä-Ketelä M, Micklefield J, Mitchell DA, Moore BS, Moreira LM, Müller R, Neilan BA, Nett M, Nielsen J, O'Gara F, Oikawa H, Osbourn A, Osburne MS, Ostash B, Payne SM, Pernodet JL, Petricek M, Piel J, Ploux O, Raaijmakers JM, Salas JA, Schmitt EK, Scott B, Seipke RF, Shen B, Sherman DH, Sivonen K, Smanski MJ, Sosio M, Stegmann E, Süssmuth RD, Tahlan K, Thomas CM, Tang Y, Truman AW, Viaud M, Walton JD, Walsh CT, Weber T, van Wezel GP, Wilkinson B, Willey JM, Wohlleben W, Wright GD, Ziemert N, Zhang C, Zotchev SB, Breitling R, Takano E, and Glöckner FO

Subjects
Alkaloids biosynthesis, Bacteria metabolism, Databases, Genetic, Fungi metabolism, Genetic Markers, International Cooperation, Metagenome, Peptide Biosynthesis, Nucleic Acid-Independent, Peptides metabolism, Plants metabolism, Polyketides metabolism, Polysaccharides biosynthesis, Terminology as Topic, Terpenes metabolism, Bacteria genetics, Computational Biology standards, Fungi genetics, Multigene Family, Plants genetics, Protein Biosynthesis
Published
2015
Full Text
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