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1. Towards the sustainable discovery and development of new antibiotics

Author

Miethke, Marcus, Pieroni, Marco, Weber, Tilmann, Brönstrup, Mark, Hammann, Peter, Halby, Ludovic, Arimondo, Paola B., Glaser, Philippe, Aigle, Bertrand, Bode, Helge B., Moreira, Rui, Li, Yanyan, Luzhetskyy, Andriy, Medema, Marnix H., Pernodet, Jean-Luc, Stadler, Marc, Tormo, Jose Ruben, Genilloud, Olga, Truman, Andrew W., Weissman, Kira J., Takano, Eriko, Sabatini, Stefano, Stegmann, Evi, Brötz-Oesterhelt, Heike, Wohlleben, Wolfgang, Seemann, Myriam, Empting, Martin, Hirsch, Anna K. H., Loretz, Brigitta, Lehr, Claus-Michael, Titz, Alexander, Herrmann, Jennifer, Jaeger, Timo, Alt, Silke, Hesterkamp, Thomas, Winterhalter, Mathias, Schiefer, Andrea, Pfarr, Kenneth, Hoerauf, Achim, Graz, Heather, Graz, Michael, Lindvall, Mika, Ramurthy, Savithri, Karlén, Anders, van Dongen, Maarten, Petkovic, Hrvoje, Keller, Andreas, Peyrane, Frederic, Donadio, Stefano, Fraisse, Laurent, Piddock, Laura J. V., Gilbert, Ian H., Moser, Heinz E., Müller, Rolf, Miethke, Marcus, Pieroni, Marco, Weber, Tilmann, Brönstrup, Mark, Hammann, Peter, Halby, Ludovic, Arimondo, Paola B., Glaser, Philippe, Aigle, Bertrand, Bode, Helge B., Moreira, Rui, Li, Yanyan, Luzhetskyy, Andriy, Medema, Marnix H., Pernodet, Jean-Luc, Stadler, Marc, Tormo, Jose Ruben, Genilloud, Olga, Truman, Andrew W., Weissman, Kira J., Takano, Eriko, Sabatini, Stefano, Stegmann, Evi, Brötz-Oesterhelt, Heike, Wohlleben, Wolfgang, Seemann, Myriam, Empting, Martin, Hirsch, Anna K. H., Loretz, Brigitta, Lehr, Claus-Michael, Titz, Alexander, Herrmann, Jennifer, Jaeger, Timo, Alt, Silke, Hesterkamp, Thomas, Winterhalter, Mathias, Schiefer, Andrea, Pfarr, Kenneth, Hoerauf, Achim, Graz, Heather, Graz, Michael, Lindvall, Mika, Ramurthy, Savithri, Karlén, Anders, van Dongen, Maarten, Petkovic, Hrvoje, Keller, Andreas, Peyrane, Frederic, Donadio, Stefano, Fraisse, Laurent, Piddock, Laura J. V., Gilbert, Ian H., Moser, Heinz E., and Müller, Rolf

Abstract

An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

Published
2021
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2. Towards the sustainable discovery and development of new antibiotics

Author

Miethke, Marcus, Pieroni, Marco, Weber, Karl Tilmann, Brönstrup, Mark, Hammann, Peter, Halby, Ludovic, Arimondo, Paola B., Glaser, Philippe, Aigle, Bertrand, Bode, Helge Björn, Moreira, Rui, Li, Yanyan, Luzhetskyy, Andriy, Medema, Marnix H., Pernodet, Jean-Luc, Stadler, Marc, Tormo, José Rubén, Genilloud, Olga, Truman, Andrew W., Weissman, Kira J., Takano, Eriko, Sabatini, Stefano, Stegmann, Evi, Brötz, Heike, Wohlleben, Wolfgang, Seemann, Myriam, Empting, Martin, Hirsch, Anna K. H., Loretz, Brigitta, Lehr, Claus-Michael, Titz, Alexander, Herrmann, Jennifer, Jäger, Timo, Alt, Silke, Hesterkamp, Thomas, Winterhalter, Mathias, Schiefer, Andrea, Pfarr, Kenneth, Hoerauf, Achim, Graz, Heather, Graz, Michael, Lindvall, Mika, Ramurthy, Savithri, Karlén, Anders, Dongen, Maarten van, Petkovic, Hrvoje, Keller, Andreas, Peyrane, Frédéric, Donadio, Stefano, Fraisse, Laurent, Piddock, Laura J. V., Gilbert, Ian H., Moser, Heinz E., Müller, Rolf, Miethke, Marcus, Pieroni, Marco, Weber, Karl Tilmann, Brönstrup, Mark, Hammann, Peter, Halby, Ludovic, Arimondo, Paola B., Glaser, Philippe, Aigle, Bertrand, Bode, Helge Björn, Moreira, Rui, Li, Yanyan, Luzhetskyy, Andriy, Medema, Marnix H., Pernodet, Jean-Luc, Stadler, Marc, Tormo, José Rubén, Genilloud, Olga, Truman, Andrew W., Weissman, Kira J., Takano, Eriko, Sabatini, Stefano, Stegmann, Evi, Brötz, Heike, Wohlleben, Wolfgang, Seemann, Myriam, Empting, Martin, Hirsch, Anna K. H., Loretz, Brigitta, Lehr, Claus-Michael, Titz, Alexander, Herrmann, Jennifer, Jäger, Timo, Alt, Silke, Hesterkamp, Thomas, Winterhalter, Mathias, Schiefer, Andrea, Pfarr, Kenneth, Hoerauf, Achim, Graz, Heather, Graz, Michael, Lindvall, Mika, Ramurthy, Savithri, Karlén, Anders, Dongen, Maarten van, Petkovic, Hrvoje, Keller, Andreas, Peyrane, Frédéric, Donadio, Stefano, Fraisse, Laurent, Piddock, Laura J. V., Gilbert, Ian H., Moser, Heinz E., and Müller, Rolf

Abstract

An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

Published
2021

3. Towards the sustainable discovery and development of new antibiotics

Author

Miethke, Marcus, Pieroni, Marco, Weber, Tilmann, Brönstrup, Mark, Hammann, Peter, Halby, Ludovic, Arimondo, Paola B., Glaser, Philippe, Aigle, Bertrand, Bode, Helge B., Moreira, Rui, Li, Yanyan, Luzhetskyy, Andriy, Medema, Marnix H., Pernodet, Jean Luc, Stadler, Marc, Tormo, José Rubén, Genilloud, Olga, Truman, Andrew W., Weissman, Kira J., Takano, Eriko, Sabatini, Stefano, Stegmann, Evi, Brötz-Oesterhelt, Heike, Wohlleben, Wolfgang, Seemann, Myriam, Empting, Martin, Hirsch, Anna K.H., Loretz, Brigitta, Lehr, Claus Michael, Titz, Alexander, Herrmann, Jennifer, Jaeger, Timo, Alt, Silke, Hesterkamp, Thomas, Winterhalter, Mathias, Schiefer, Andrea, Pfarr, Kenneth, Hoerauf, Achim, Graz, Heather, Graz, Michael, Lindvall, Mika, Ramurthy, Savithri, Karlén, Anders, van Dongen, Maarten, Petkovic, Hrvoje, Keller, Andreas, Peyrane, Frédéric, Donadio, Stefano, Fraisse, Laurent, Piddock, Laura J.V., Gilbert, Ian H., Moser, Heinz E., Müller, Rolf, Miethke, Marcus, Pieroni, Marco, Weber, Tilmann, Brönstrup, Mark, Hammann, Peter, Halby, Ludovic, Arimondo, Paola B., Glaser, Philippe, Aigle, Bertrand, Bode, Helge B., Moreira, Rui, Li, Yanyan, Luzhetskyy, Andriy, Medema, Marnix H., Pernodet, Jean Luc, Stadler, Marc, Tormo, José Rubén, Genilloud, Olga, Truman, Andrew W., Weissman, Kira J., Takano, Eriko, Sabatini, Stefano, Stegmann, Evi, Brötz-Oesterhelt, Heike, Wohlleben, Wolfgang, Seemann, Myriam, Empting, Martin, Hirsch, Anna K.H., Loretz, Brigitta, Lehr, Claus Michael, Titz, Alexander, Herrmann, Jennifer, Jaeger, Timo, Alt, Silke, Hesterkamp, Thomas, Winterhalter, Mathias, Schiefer, Andrea, Pfarr, Kenneth, Hoerauf, Achim, Graz, Heather, Graz, Michael, Lindvall, Mika, Ramurthy, Savithri, Karlén, Anders, van Dongen, Maarten, Petkovic, Hrvoje, Keller, Andreas, Peyrane, Frédéric, Donadio, Stefano, Fraisse, Laurent, Piddock, Laura J.V., Gilbert, Ian H., Moser, Heinz E., and Müller, Rolf

Abstract

An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations. [Figure not available: see fulltext.]

Published
2021

4. A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin

Author

Vučićević, Jelica, Vučićević, Jelica, Srdić-Rajić, Tatjana, Pieroni, Marco, Laurila, Jonne M. M., Perović, Vladimir, Tassini, Sabrina, Azzali, Elisa, Costantino, Gabriele, Glisić, Sanja, Agbaba, Danica, Scheinin, Mika, Nikolić, Katarina, Radi, Marco, Veljković, Nevena, Vučićević, Jelica, Vučićević, Jelica, Srdić-Rajić, Tatjana, Pieroni, Marco, Laurila, Jonne M. M., Perović, Vladimir, Tassini, Sabrina, Azzali, Elisa, Costantino, Gabriele, Glisić, Sanja, Agbaba, Danica, Scheinin, Mika, Nikolić, Katarina, Radi, Marco, and Veljković, Nevena

Abstract

The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I-1-type imidazoline receptors (I-1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from alpha(2)-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine- derived compounds with anticancer potential and devoid of alpha(2)-adrenoceptor effects by means of ligand-and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to alpha(2)-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.

Published
2016

5. A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin

Author

Vucicevic, Jelica, Srdić-Rajić, Tatjana, Pieroni, Marco, Laurila, Jonne M. M., Perović, Vladimir R., Tassini, Sabrina, Azzali, Elisa, Costantino, Gabriele, Glišić, Sanja, Agbaba, Danica, Scheinin, Mika, Nikolić, Katarina M., Radi, Marco, Veljković, Nevena V., Vucicevic, Jelica, Srdić-Rajić, Tatjana, Pieroni, Marco, Laurila, Jonne M. M., Perović, Vladimir R., Tassini, Sabrina, Azzali, Elisa, Costantino, Gabriele, Glišić, Sanja, Agbaba, Danica, Scheinin, Mika, Nikolić, Katarina M., Radi, Marco, and Veljković, Nevena V.

Abstract

The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I-1-type imidazoline receptors (I-1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from alpha(2)-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine- derived compounds with anticancer potential and devoid of alpha(2)-adrenoceptor effects by means of ligand-and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to alpha(2)-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers. (C) 2016 Elsevier Ltd. All rights reserved.

Published
2016

6. A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin

Author

Vučićević, Jelica, Srdić-Rajić, Tatjana, Pieroni, Marco, Laurila, Jonne M. M., Perović, Vladimir R., Tassini, Sabrina, Azzali, Elisa, Costantino, Gabriele, Glišić, Sanja, Agbaba, Danica, Scheinin, Mika, Nikolić, Katarina M., Radi, Marco, Veljković, Nevena V., Vučićević, Jelica, Srdić-Rajić, Tatjana, Pieroni, Marco, Laurila, Jonne M. M., Perović, Vladimir R., Tassini, Sabrina, Azzali, Elisa, Costantino, Gabriele, Glišić, Sanja, Agbaba, Danica, Scheinin, Mika, Nikolić, Katarina M., Radi, Marco, and Veljković, Nevena V.

Abstract

The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I-1-type imidazoline receptors (I-1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from alpha(2)-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine- derived compounds with anticancer potential and devoid of alpha(2)-adrenoceptor effects by means of ligand-and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to alpha(2)-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers. (C) 2016 Elsevier Ltd. All rights reserved.

Published
2016

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