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42 results on '"Schmitt, Esther K"'

1. A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin

Author

Qiu, Deyun, Pei, Jinxin V., Rosling, James E. O., Thathy, Vandana, Li, Dongdi, Xue, Yi, Tanner, John D., Penington, Jocelyn Sietsma, Aw, Yi Tong Vincent, Aw, Jessica Yi Han, Xu, Guoyue, Tripathi, Abhai K., Gnadig, Nina F., Yeo, Tomas, Fairhurst, Kate J., Stokes, Barbara H., Murithi, James M., Kümpornsin, Krittikorn, Hasemer, Heath, Dennis, Adelaide S. M., Ridgway, Melanie C., Schmitt, Esther K., Straimer, Judith, Papenfuss, Anthony T., Lee, Marcus C. S., Corry, Ben, Sinnis, Photini, Fidock, David A., van Dooren, Giel G., Kirk, Kiaran, and Lehane, Adele M.

Published
2022
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2. Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa

Author

Ndayisaba, Gilles, Yeka, Adoke, Asante, Kwaku Poku, Grobusch, Martin P., Karita, Etienne, Mugerwa, Henry, Asiimwe, Stephen, Oduro, Abraham, Fofana, Bakary, Doumbia, Seydou, Jain, Jay Prakash, Barsainya, Sarita, Kullak-Ublick, Gerd A., Su, Guoqin, Schmitt, Esther K., Csermak, Katalin, Gandhi, Preetam, and Hughes, David

Published
2021
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3. Global impact of human fasciolosis.

Author

Gandhi, Preetam, primary, Chandra, Richa, additional, Schmitt, Esther K., additional, Chen, Chien-Wei, additional, Samantray, Sanjay, additional, Venishetty, Vinay Kumar, additional, and Hughes, David, additional

Published
2021
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4. The Novolactone Natural Product Disrupts the Allosteric Regulation of Hsp70

Author

Hassan, A. Quamrul, Kirby, Christina A., Zhou, Wenlai, Schuhmann, Tim, Kityk, Roman, Kipp, D. Randal, Baird, Jason, Chen, Jinyun, Chen, Yaoyu, Chung, Franklin, Hoepfner, Dominic, Movva, N. Rao, Pagliarini, Raymond, Petersen, Frank, Quinn, Christopher, Quinn, Douglas, Riedl, Ralph, Schmitt, Esther K., Schitter, Anne, Stams, Travis, Studer, Christian, Fortin, Pascal D., Mayer, Matthias P., and Sadlish, Heather

Published
2015
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7. Spiroindolones, a Potent Compound Class for the Treatment of Malaria

Author

Rottmann, Matthias, McNamara, Case, Yeung, Bryan K. S., Lee, Marcus C. S., Zou, Bin, Russell, Bruce, Seite, Patrick, Plouffe, David M., Dharia, Neekesh V., Tan, Jocelyn, Cohen, Steven B., Spencer, Kathryn R., González-Páez, Gonzalo E., Lakshminarayana, Suresh B., Goh, Anne, Suwanarusk, Rossarin, Jegla, Timothy, Schmitt, Esther K., Beck, Hans-Peter, Brun, Reto, Nosten, Francois, Renia, Laurent, Dartois, Veronique, Keller, Thomas H., Fidock, David A., Winzeler, Elizabeth A., and Diagana, Thierry T.

Published
2010

9. Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria

Author

Schmitt, Esther K, primary, Ndayisaba, Gilles, additional, Yeka, Adoke, additional, Asante, Kwaku Poku, additional, Grobusch, Martin P, additional, Karita, Etienne, additional, Mugerwa, Henry, additional, Asiimwe, Stephen, additional, Oduro, Abraham, additional, Fofana, Bakary, additional, Doumbia, Seydou, additional, Su, Guoqin, additional, Csermak Renner, Katalin, additional, Venishetty, Vinay Kumar, additional, Sayyed, Sarfaraz, additional, Straimer, Judith, additional, Demin, Ivan, additional, Barsainya, Sarita, additional, Boulton, Caroline, additional, and Gandhi, Preetam, additional

Published
2021
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11. Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria.

Author

Schmitt, Esther K, Ndayisaba, Gilles, Yeka, Adoke, Asante, Kwaku Poku, Grobusch, Martin P, Karita, Etienne, Mugerwa, Henry, Asiimwe, Stephen, Oduro, Abraham, Fofana, Bakary, Doumbia, Seydou, Su, Guoqin, Renner, Katalin Csermak, Venishetty, Vinay Kumar, Sayyed, Sarfaraz, Straimer, Judith, Demin, Ivan, Barsainya, Sarita, Boulton, Caroline, and Gandhi, Preetam

Subjects
*DRUG therapy for malaria, *DRUG efficacy, *BIOMARKERS, *RESEARCH, *PROTOZOA, *PARASITOLOGY, *DRUG resistance, *MOLECULAR pathology, *MALARIA, *RANDOMIZED controlled trials, *TREATMENT failure, *MICROBIOLOGICAL techniques, *DESCRIPTIVE statistics, *ANTIMALARIALS, *POLYMERASE chain reaction, *EVALUATION, *ADULTS
Abstract

Background Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere). Methods This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)–corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. Results All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. Conclusions Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. Clinical Trials Registration ClinicalTrials.gov (NCT03334747). [ABSTRACT FROM AUTHOR]

Published
2022
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12. High Prevalence of Plasmodium falciparum K13 Mutations in Rwanda Is Associated With Slow Parasite Clearance After Treatment With Artemether-Lumefantrine.

Author

Straimer, Judith, Gandhi, Preetam, Renner, Katalin Csermak, and Schmitt, Esther K

Subjects
DRUG therapy for malaria, PROTEINS, PROTOZOA, RESEARCH, GENETIC mutation, ANIMAL experimentation, RESEARCH methodology, DRUG resistance, EVALUATION research, MALARIA, COMPARATIVE studies, RANDOMIZED controlled trials, DISEASE prevalence, RESEARCH funding, ANTIMALARIALS, PARASITES, PHARMACODYNAMICS
Abstract

In Southeast Asia, mutations in the Plasmodium falciparum K13 gene have led to delayed parasite clearance and treatment failures in patients with malaria receiving artemisinin combination therapies. Until recently, relevant K13 mutations had been mostly absent from Africa. Between 2018 and 2019, a phase 2 clinical study with 186 patients was conducted in Mali, Gabon, Ghana, Uganda, and Rwanda. Patients with malaria were randomized and treated with artemether-lumefantrine or cipargamin. Here we report an allele frequency of 22% for R561H in Rwanda and associated delayed parasite clearance. Notwithstanding, efficacy of artemether-lumefantrine remained high in Rwanda, with a 94.4% polymerase chain reaction-corrected cure rate. [ABSTRACT FROM AUTHOR]

Published
2022
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18. Ribosomally synthesized thiopeptide antibiotics targeting elongation factor Tu

Author

Morris, Rowan P., Leeds, Jennifer A., Naegeli, Hans Ulrich, Oberer, Lukas, Memmert, Klaus, Weber, Eric, LaMarche, Matthew J., Parker, Christian N., Burrer, Nathalie, Esterow, Stacey, Hein, Andreas E., Schmitt, Esther K., and Krastel, Philipp

Subjects
Thiazides -- Chemical properties, Peptides -- Chemical properties, Actinomycetes -- Chemical properties, Chemistry
Abstract

The thiomuracins, a novel family of thiopeptides produced by a rare-actinomycete bacterium typed as a Nonomuraea species, are identified by a screen for inhibition of growth of the bacterial pathogen Staphylococcus aureus. The target of the thiomuracins is identified as bacterial Elongation Factor Tu (EF-Tu) and the thiomuracins have a low propensity for selecting for antibiotic resistance and confer no measurable cross-resistance to antibiotics in clinical use.

Published
2009

19. Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation

Author

Wlodarska, Marta, primary, Luo, Chengwei, additional, Kolde, Raivo, additional, d’Hennezel, Eva, additional, Annand, John W., additional, Heim, Cortney E., additional, Krastel, Philipp, additional, Schmitt, Esther K., additional, Omar, Abdifatah S., additional, Creasey, Elizabeth A., additional, Garner, Ashley L., additional, Mohammadi, Sina, additional, O’Connell, Daniel J., additional, Abubucker, Sahar, additional, Arthur, Timothy D., additional, Franzosa, Eric A., additional, Huttenhower, Curtis, additional, Murphy, Leon O., additional, Haiser, Henry J., additional, Vlamakis, Hera, additional, Porter, Jeffrey A., additional, and Xavier, Ramnik J., additional

Published
2017
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20. 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

21. 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

22. 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

23. Inside Cover: Gift from Nature: Cyclomarin A Kills Mycobacteria and Malaria Parasites by Distinct Modes of Action (ChemBioChem 17/2015)

Author

Bürstner, Nathalie, primary, Roggo, Silvio, additional, Ostermann, Nils, additional, Blank, Jutta, additional, Delmas, Cecile, additional, Freuler, Felix, additional, Gerhartz, Bernd, additional, Hinniger, Alexandra, additional, Hoepfner, Dominic, additional, Liechty, Brigitta, additional, Mihalic, Manuel, additional, Murphy, Jason, additional, Pistorius, Dominik, additional, Rottmann, Matthias, additional, Thomas, Jason R., additional, Schirle, Markus, additional, and Schmitt, Esther K., additional

Published
2015
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25. Gift from Nature: Cyclomarin A Kills Mycobacteria and Malaria Parasites by Distinct Modes of Action

Author

Bürstner, Nathalie, primary, Roggo, Silvio, additional, Ostermann, Nils, additional, Blank, Jutta, additional, Delmas, Cecile, additional, Freuler, Felix, additional, Gerhartz, Bernd, additional, Hinniger, Alexandra, additional, Hoepfner, Dominic, additional, Liechty, Brigitta, additional, Mihalic, Manuel, additional, Murphy, Jason, additional, Pistorius, Dominik, additional, Rottmann, Matthias, additional, Thomas, Jason R., additional, Schirle, Markus, additional, and Schmitt, Esther K., additional

Published
2015
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26. Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti‐Cancer Properties

Author

Krastel, Philipp, primary, Roggo, Silvio, additional, Schirle, Markus, additional, Ross, Nathan T., additional, Perruccio, Francesca, additional, Aspesi, Peter, additional, Aust, Thomas, additional, Buntin, Kathrin, additional, Estoppey, David, additional, Liechty, Brigitta, additional, Mapa, Felipa, additional, Memmert, Klaus, additional, Miller, Howard, additional, Pan, Xuewen, additional, Riedl, Ralph, additional, Thibaut, Christian, additional, Thomas, Jason, additional, Wagner, Trixie, additional, Weber, Eric, additional, Xie, Xiaobing, additional, Schmitt, Esther K., additional, and Hoepfner, Dominic, additional

Published
2015
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27. High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions

Author

Hoepfner, Dominic, primary, Helliwell, Stephen B., additional, Sadlish, Heather, additional, Schuierer, Sven, additional, Filipuzzi, Ireos, additional, Brachat, Sophie, additional, Bhullar, Bhupinder, additional, Plikat, Uwe, additional, Abraham, Yann, additional, Altorfer, Marc, additional, Aust, Thomas, additional, Baeriswyl, Lukas, additional, Cerino, Raffaele, additional, Chang, Lena, additional, Estoppey, David, additional, Eichenberger, Juerg, additional, Frederiksen, Mathias, additional, Hartmann, Nicole, additional, Hohendahl, Annika, additional, Knapp, Britta, additional, Krastel, Philipp, additional, Melin, Nicolas, additional, Nigsch, Florian, additional, Oakeley, Edward J., additional, Petitjean, Virginie, additional, Petersen, Frank, additional, Riedl, Ralph, additional, Schmitt, Esther K., additional, Staedtler, Frank, additional, Studer, Christian, additional, Tallarico, John A., additional, Wetzel, Stefan, additional, Fishman, Mark C., additional, Porter, Jeffrey A., additional, and Movva, N. Rao, additional

Published
2014
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28. Selective and Specific Inhibition of the Plasmodium falciparum Lysyl-tRNA Synthetase by the Fungal Secondary Metabolite Cladosporin

Author

Hoepfner, Dominic, primary, McNamara, Case W., additional, Lim, Chek Shik, additional, Studer, Christian, additional, Riedl, Ralph, additional, Aust, Thomas, additional, McCormack, Susan L., additional, Plouffe, David M., additional, Meister, Stephan, additional, Schuierer, Sven, additional, Plikat, Uwe, additional, Hartmann, Nicole, additional, Staedtler, Frank, additional, Cotesta, Simona, additional, Schmitt, Esther K., additional, Petersen, Frank, additional, Supek, Frantisek, additional, Glynne, Richard J., additional, Tallarico, John A., additional, Porter, Jeffrey A., additional, Fishman, Mark C., additional, Bodenreider, Christophe, additional, Diagana, Thierry T., additional, Movva, N. Rao, additional, and Winzeler, Elizabeth A., additional

Published
2012
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29. The Natural Product Cyclomarin Kills Mycobacterium Tuberculosis by Targeting the ClpC1 Subunit of the Caseinolytic Protease

Author

Schmitt, Esther K., primary, Riwanto, Meliana, additional, Sambandamurthy, Vasan, additional, Roggo, Silvio, additional, Miault, Charlotte, additional, Zwingelstein, Christian, additional, Krastel, Philipp, additional, Noble, Christian, additional, Beer, David, additional, Rao, Srinivasa P. S., additional, Au, Melvin, additional, Niyomrattanakit, Pornwaratt, additional, Lim, Viviam, additional, Zheng, Jun, additional, Jeffery, Douglas, additional, Pethe, Kevin, additional, and Camacho, Luis R., additional

Published
2011
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30. Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria

Author

Yeung, Bryan K. S., primary, Zou, Bin, additional, Rottmann, Matthias, additional, Lakshminarayana, Suresh B., additional, Ang, Shi Hua, additional, Leong, Seh Yong, additional, Tan, Jocelyn, additional, Wong, Josephine, additional, Keller-Maerki, Sonja, additional, Fischli, Christoph, additional, Goh, Anne, additional, Schmitt, Esther K., additional, Krastel, Philipp, additional, Francotte, Eric, additional, Kuhen, Kelli, additional, Plouffe, David, additional, Henson, Kerstin, additional, Wagner, Trixie, additional, Winzeler, Elizabeth A., additional, Petersen, Frank, additional, Brun, Reto, additional, Dartois, Veronique, additional, Diagana, Thierry T., additional, and Keller, Thomas H., additional

Published
2010
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35. CPCR1, but not its interacting transcription factor AcFKH1, controls fungal arthrospore formation inAcremonium chrysogenum.

Author

Hoff, Birgit, Schmitt, Esther K., and Kück, Ulrich

Subjects
*ACREMONIUM, *FUNGAL morphogenesis, *SECONDARY metabolism, *TRANSCRIPTION factors, *CEPHALOSPORINS, *MICROBIAL proteins
Abstract

Fungal morphogenesis and secondary metabolism are frequently associated; however, the molecular determinants connecting both processes remain largely undefined. Here we demonstrate that CPCR1 (cephalosporin C regulator 1 fromAcremonium chrysogenum), a member of the winged helix/regulator factor X (RFX) transcription factor family that regulates cephalosporin C biosynthesis, also controls morphological development in theβ-lactam producerA. chrysogenum. The use of a disruption strain, multicopy strains as well as several recombinant control strains revealed that CPCR1 is required for hyphal fragmentation, and thus the formation of arthrospores. In aΔ cpcR1disruption strain that exhibits only hyphal growth, the wild-typecpcR1gene was able to restore arthrospore formation; a phenomenon not observed forΔ cpcR1derivatives or non-related genes. The intracellular expression ofcpcR1, and control genes (pcbC,egfp) was determined byin vivomonitoring of fluorescent protein fusions. Further, the role of the forkhead transcription factor AcFKH1, which directly interacts with CPCR1, was studied by generating anAcfkh1knockout strain. In contrast to CPCR1, AcFKH1 is not directly involved in the fragmentation of hyphae. Instead, the presence of AcFKH1 seems to be necessary for CPCR1 function inA. chrysogenummorphogenesis, as overexpression of a functionalcpcR1gene in aΔ Acfkh1background has no effect on arthrospore formation. Moreover, strains lackingAcfkh1exhibit defects in cell separation, indicating an involvement of the forkhead transcription factor in mycelial growth ofA. chrysogenum. Our data offer the potential to control fungal growth in biotechnical processes that require defined morphological stages for optimal production yields. [ABSTRACT FROM AUTHOR]

Published
2005
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36. Winged helix transcription factor CPCR1 is involved in regulation of beta-lactam biosynthesis in the fungus Acremonium chrysogenum.

Author

Schmitt, Esther K, Bunse, Astrid, Janus, Danielle, Hoff, Birgit, Friedlin, Ernst, Kürnsteiner, Hubert, and Kück, Ulrich

Abstract

Winged helix transcription factors, including members of the forkhead and the RFX subclasses, are characteristic for the eukaryotic domains in animals and fungi but seem to be missing in plants. In this study, in vitro and in vivo approaches were used to determine the functional role of the RFX transcription factor CPCR1 from the filamentous fungus Acremonium chrysogenum in cephalosporin C biosynthesis. Gel retardation analyses were applied to identify new binding sites of the transcription factor in an intergenic promoter region of cephalosporin C biosynthesis genes. Here, we illustrate that CPCR1 recognizes and binds at least two sequences in the intergenic region between the pcbAB and pcbC genes. The in vivo relevance of the two sequences for gene activation was demonstrated by using pcbC promoter-lacZ fusions in A. chrysogenum. The deletion of both CPCR1 binding sites resulted in an extensive reduction of reporter gene activity in transgenic strains (to 12% of the activity level of the control). Furthermore, Acremonium transformants with multiple copies of the cpcR1 gene and knockout strains support the idea of CPCR1 being a regulator of cephalosporin C biosynthesis gene expression. Significant differences in pcbC gene transcript levels were obtained with the knockout transformants. More-than-twofold increases in the pcbC transcript level at 24 and 36 h of cultivation were followed by a reduction to approximately 80% from 48 to 96 h in the knockout strain. The overall levels of the production of cephalosporin C were identical in transformed and nontransformed strains; however, the knockout strains showed a striking reduction in the level of the biosynthesis of intermediate penicillin N to less than 20% of that of the recipient strain. We were able to show that the complementation of the cpcR1 gene in the knockout strains reverses pcbC transcript and penicillin N amounts to levels comparable to those in the control. These results clearly indicate the involvement of CPCR1 in the regulation of cephalosporin C biosynthesis. However, the complexity of the data points to a well-controlled or even functional redundant network of transcription factors, with CPCR1 being only one player within this process.

Published
2004

37. Winged Helix Transcription Factor CPCR1 Is Involved in Regulation of ß-Lactam Biosynthesis in the Fungus Acremonium chrysogenum

Author

Schmitt, Esther K., Bunse, Astrid, Janus, Danielle, Hoff, Birgit, Friedlin, Ernst, Ku¨rnsteiner, Hubert, and Ku¨ck, Ulrich

Abstract

ABSTRACTWinged helix transcription factors, including members of the forkhead and the RFX subclasses, are characteristic for the eukaryotic domains in animals and fungi but seem to be missing in plants. In this study, in vitro and in vivo approaches were used to determine the functional role of the RFX transcription factor CPCR1 from the filamentous fungus Acremonium chrysogenumin cephalosporin C biosynthesis. Gel retardation analyses were applied to identify new binding sites of the transcription factor in an intergenic promoter region of cephalosporin C biosynthesis genes. Here, we illustrate that CPCR1 recognizes and binds at least two sequences in the intergenic region between the pcbABand pcbCgenes. The in vivo relevance of the two sequences for gene activation was demonstrated by using pcbCpromoter-lacZfusions in A. chrysogenum. The deletion of both CPCR1 binding sites resulted in an extensive reduction of reporter gene activity in transgenic strains (to 12% of the activity level of the control). Furthermore, Acremoniumtransformants with multiple copies of the cpcR1gene and knockout strains support the idea of CPCR1 being a regulator of cephalosporin C biosynthesis gene expression. Significant differences in pcbCgene transcript levels were obtained with the knockout transformants. More-than-twofold increases in the pcbCtranscript level at 24 and 36 h of cultivation were followed by a reduction to approximately 80% from 48 to 96 h in the knockout strain. The overall levels of the production of cephalosporin C were identical in transformed and nontransformed strains; however, the knockout strains showed a striking reduction in the level of the biosynthesis of intermediate penicillin N to less than 20% of that of the recipient strain. We were able to show that the complementation of the cpcR1gene in the knockout strains reverses pcbCtranscript and penicillin N amounts to levels comparable to those in the control. These results clearly indicate the involvement of CPCR1 in the regulation of cephalosporin C biosynthesis. However, the complexity of the data points to a well-controlled or even functional redundant network of transcription factors, with CPCR1 being only one player within this process.

Published
2004
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38. Additional file 1 of Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa

Author

Ndayisaba, Gilles, Yeka, Adoke, Asante, Kwaku Poku, Grobusch, Martin P., Karita, Etienne, Mugerwa, Henry, Asiimwe, Stephen, Oduro, Abraham, Fofana, Bakary, Doumbia, Seydou, Jain, Jay Prakash, Barsainya, Sarita, Kullak-Ublick, Gerd A., Su, Guoqin, Schmitt, Esther K., Csermak, Katalin, Gandhi, Preetam, and Hughes, David

Subjects
3. Good health
Abstract

Additional file 1. Supplement Hepatic safety and tolerability of cipargamin (KAE609).

39. Additional file 1 of Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa

Author

Ndayisaba, Gilles, Yeka, Adoke, Asante, Kwaku Poku, Grobusch, Martin P., Karita, Etienne, Mugerwa, Henry, Asiimwe, Stephen, Oduro, Abraham, Fofana, Bakary, Doumbia, Seydou, Jain, Jay Prakash, Barsainya, Sarita, Kullak-Ublick, Gerd A., Su, Guoqin, Schmitt, Esther K., Csermak, Katalin, Gandhi, Preetam, and Hughes, David

Subjects
3. Good health
Abstract

Additional file 1. Supplement Hepatic safety and tolerability of cipargamin (KAE609).

40. 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
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41. Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties.

Author

Krastel P, Roggo S, Schirle M, Ross NT, Perruccio F, Aspesi P Jr, Aust T, Buntin K, Estoppey D, Liechty B, Mapa F, Memmert K, Miller H, Pan X, Riedl R, Thibaut C, Thomas J, Wagner T, Weber E, Xie X, Schmitt EK, and Hoepfner D

Subjects
Antifungal Agents chemistry, Antifungal Agents pharmacology, Antineoplastic Agents pharmacology, Apoptosis drug effects, Candida albicans drug effects, Genomics methods, Humans, Macrocyclic Compounds chemistry, Molecular Structure, Neoplasms drug therapy, Peptide Elongation Factor 1 genetics, Peptide Elongation Factor 1 metabolism, Proteomics methods, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Macrocyclic Compounds pharmacology, Myxococcales physiology, Neoplasms pathology, Peptide Elongation Factor 1 antagonists & inhibitors
Abstract

Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti-fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF-1α) as the primary target for this compound class. Nannocystin A (1) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site of 1 with the anti-cancer compound didemnin B on EF-1α. This myxobacterial chemotype thus offers an interesting starting point for further investigations of the potential of therapeutics targeting elongation factor 1., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2015
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42. Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria.

Author

Yeung BK, Zou B, Rottmann M, Lakshminarayana SB, Ang SH, Leong SY, Tan J, Wong J, Keller-Maerki S, Fischli C, Goh A, Schmitt EK, Krastel P, Francotte E, Kuhen K, Plouffe D, Henson K, Wagner T, Winzeler EA, Petersen F, Brun R, Dartois V, Diagana TT, and Keller TH

Subjects
Animals, Antimalarials pharmacokinetics, Antimalarials pharmacology, Carbolines pharmacokinetics, Carbolines pharmacology, Cell Line, Crystallography, X-Ray, Humans, In Vitro Techniques, Indoles pharmacokinetics, Indoles pharmacology, Malaria drug therapy, Mice, Microsomes, Liver metabolism, Molecular Structure, Plasmodium berghei, Spiro Compounds pharmacokinetics, Spiro Compounds pharmacology, Stereoisomerism, Structure-Activity Relationship, Antimalarials chemical synthesis, Carbolines chemical synthesis, Indoles chemical synthesis, Spiro Compounds chemical synthesis
Abstract

The antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC(50) of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC(50) = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.

Published
2010
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