Search

Your search keyword '"Hacker, Stephan M."' showing total 158 results
Start Over Author "Hacker, Stephan M."
158 results on '"Hacker, Stephan M."'

2. A proteome-wide atlas of lysine-reactive chemistry

Author

Abbasov, Mikail E., Kavanagh, Madeline E., Ichu, Taka-Aki, Lazear, Michael R., Tao, Yongfeng, Crowley, Vincent M., am Ende, Christopher W., Hacker, Stephan M., Ho, Jordan, Dix, Melissa M., Suciu, Radu, Hayward, Matthew M., Kiessling, Laura L., and Cravatt, Benjamin F.

Published
2021
Full Text
View/download PDF

3. Bioresponsive pseudoGlucosinolates (psGSLs) release Isothiocyanates (ITCs) in the Presence of Nitroreductases

Author

Jimidar, Claire C., primary, Ganskow, Charity S. G., additional, Kagho, Mervic D., additional, Chakrabarti, Aishi, additional, Wiese, Lorenz, additional, Zollo, Michael, additional, Beutling, Ulrike, additional, Brönstrup, Mark, additional, Sieber, Stephan A., additional, Hacker, Stephan M., additional, and Klahn, Philipp, additional

Published
2024
Full Text
View/download PDF

5. Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms

Author

Le, Philipp, Kunold, Elena, Macsics, Robert, Rox, Katharina, Jennings, Megan C., Ugur, Ilke, Reinecke, Maria, Chaves-Moreno, Diego, Hackl, Mathias W., Fetzer, Christian, Mandl, Franziska A. M., Lehmann, Johannes, Korotkov, Vadim S., Hacker, Stephan M., Kuster, Bernhard, Antes, Iris, Pieper, Dietmar H., Rohde, Manfred, Wuest, William M., Medina, Eva, and Sieber, Stephan A.

Published
2020
Full Text
View/download PDF

7. Phosphate-Modified Nucleotides for Monitoring Enzyme Activity

Author

Ermert, Susanne, Marx, Andreas, Hacker, Stephan M., Wong, Wai-Yeung, Editor-in-chief, Olivucci, Massimo, Editor-in-chief, Bayley, Hagan, Series editor, Houk, Kendall N., Series editor, Hughes, Greg, Series editor, Hunter, Christopher A., Series editor, Hwang, Seong-Ju, Series editor, Ishihara, Kazuaki, Series editor, Kirchner, Barbara, Series editor, Krische, Michael J., Series editor, Larsen, Delmar, Series editor, Lehn, Jean-Marie, Series editor, Luque, Rafael, Series editor, Siegel, Jay S., Series editor, Thiem, Joachim, Series editor, Venturi, Margherita, Series editor, Wong, Chi-Huey, Series editor, Wong, Henry N.C., Series editor, Yam, Vivian Wing-Wah, Series editor, Yan, Chunhua, Series editor, You, Shu-Li, Series editor, and Jessen, Henning Jacob, editor

Published
2017
Full Text
View/download PDF

13. A modular concept for enzymatically activatable caged electrophiles & Chemoproteomic analysis of the covalent ligandability of Moraxella catarrhalis

Author

Sieber, Stephan A. (Prof. Dr.), Sieber, Stephan A. (Prof. Dr.);Hacker, Stephan M. (Prof. Dr.), Zollo, Michael, Sieber, Stephan A. (Prof. Dr.), Sieber, Stephan A. (Prof. Dr.);Hacker, Stephan M. (Prof. Dr.), and Zollo, Michael

Abstract

Two complementary strategies to tackle the growing health crisis of antibiotic resistance were pursued in this thesis. A modular concept of caged electrophiles that are selectively liberated in bacteria by enzymatic activation was established. This strategy has the potential to deliver antibiotics with reduced side-effects and resistance formation. For the development of novel narrow-spectrum antibiotics, the covalent ligandability of cysteines in the pathogen Moraxella catarrhalis was profiled and covalent binding was validated for three essential proteins., In dieser Arbeit wurden zwei komplementäre Strategien zur Bekämpfung der Antibiotikakrise verfolgt. Zur Vermeidung von Nebenwirkungen und Resistenzbildung wurde ein modulares Konzept geschützter Elektrophile erarbeitet, welches das Potenzial hat, Antibiotika selektiv in Bakterien durch enzymatische Aktivierung freizusetzen. Zur Entwicklung neuer pathogenspezifischer Antibiotika wurde die kovalente Adressierbarkeit von Cysteinen im Krankheitserreger Moraxella catarrhalis untersucht und die kovalente Bindung dreier essenzieller Proteine validiert.

Published
2023

15. Development of electrophiles and chemoproteomic methods for the exploration of the ligandability of bacterial proteomes

Author

Hacker, Stephan M. (Dr.), Hacker, Stephan M. (Dr.);Zeymer, Cathleen (Prof. Dr.);Lang, Kathrin (Prof. Dr.), Zanon, Patrick R. A., Hacker, Stephan M. (Dr.), Hacker, Stephan M. (Dr.);Zeymer, Cathleen (Prof. Dr.);Lang, Kathrin (Prof. Dr.), and Zanon, Patrick R. A.

Abstract

The herein developed chemoproteomic isoDTB-ABPP platform streamlines the identification of binding sites of covalent ligands across bacterial proteomes, providing starting points for the development of novel antibiotics. Moreover, the described advances in the profiling of nucleophilic amino acids other than cysteine will help to expand the target space of covalent ligands and thus foster the development of antibiotics with new modes-of-action., Die hier entwickelte chemoproteomische isoDTB-ABPP-Plattform ermöglicht die proteomweite Identifizierung von Bindestellen kovalenter Liganden und liefert so Ansatzpunkte für die Entwicklung neuartiger Antibiotika. Zudem werden die beschriebenen Fortschritte in der Untersuchung anderer nukleophiler Aminosäuren als Cystein dazu beitragen, die Anzahl potentieller Zielstrukturen kovalenter Liganden zu erhöhen und so die Entwicklung von Antibiotika mit neuartigen Wirkmechanismen fördern.

Published
2021

17. SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

Author

Demange, Pascal, primary, Joly, Etienne, primary, Marcoux, Julien, primary, Zanon, Patrick RA, additional, Listunov, Dymytrii, additional, Rullière, Pauline, additional, Barthes, Cécile, additional, Noirot, Céline, additional, Izquierdo, Jean-Baptiste, additional, Rozié, Alexandrine, additional, Pradines, Karen, additional, Hee, Romain, additional, de Brito, Maria Vieira, additional, Marcellin, Marlène, additional, Serre, Remy-Felix, additional, Bouchez, Olivier, additional, Burlet-Schiltz, Odile, additional, Oliveira, Maria Conceição Ferreira, additional, Ballereau, Stéphanie, additional, Bernardes-Génisson, Vania, additional, Maraval, Valérie, additional, Calsou, Patrick, additional, Hacker, Stephan M, additional, Génisson, Yves, additional, Chauvin, Remi, additional, and Britton, Sébastien, additional

Published
2022
Full Text
View/download PDF

18. The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21

Author

Svenningsen, Esben B., Ottosen, Rasmus N., Jørgensen, Katrine H., Nisavic, Marija, Larsen, Camilla K., Hansen, Bente K., Wang, Yong, Lindorff-Larsen, Kresten, Tørring, Thomas, Hacker, Stephan M., Palmfeldt, Johan, Poulsen, Thomas B., Svenningsen, Esben B., Ottosen, Rasmus N., Jørgensen, Katrine H., Nisavic, Marija, Larsen, Camilla K., Hansen, Bente K., Wang, Yong, Lindorff-Larsen, Kresten, Tørring, Thomas, Hacker, Stephan M., Palmfeldt, Johan, and Poulsen, Thomas B.

Abstract

Covalently acting compounds experience a strong interest within chemical biology both as molecular probes in studies of fundamental biological mechanisms and/or as novel drug candidates. In this context, the identification of new classes of reactive groups is particularly important as these can expose novel reactivity modes and, consequently, expand the ligandable proteome. Here, we investigated the electrophilic reactivity of the 3-acyl-5-hydroxy-1,5-dihydro-2H-pyrrole-2-one (AHPO) scaffold, a heterocyclic motif that is e.g. present in various bioactive natural products. Our investigations were focused on the compound MT-21 - a simplified structural analogue of the natural product epolactaene - which is known to have both neurotrophic activity and ability to trigger apoptotic cell death. We found that the central N-acyl hemiaminal group of MT-21 can function as an electrophilic centre enabling divergent reactivity with both amine- and thiol-based nucleophiles, which furthermore translated to reactivity with proteins in both cell lysates and live cells. We found that in live cells MT-21 strongly engaged the lipid transport protein fatty acid-binding protein 5 (FABP5) by direct binding to a cysteine residue in the bottom of the ligand binding pocket. Through preparation of a series of MT-21 derivatives, we probed the specificity of this interaction which was found to be strongly dependent on subtle structural changes. Our study suggests that MT-21 may be employed as a tool compound in future studies of the biology of FABP5, which remains incompletely understood. Furthermore, our study has also made clear that other natural products containing the AHPO-motif may likewise possess covalent reactivity and that this property may underlie their biological activity.

Published
2022

19. Author response: SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

Author

Demange, Pascal, primary, Joly, Etienne, primary, Marcoux, Julien, primary, Zanon, Patrick RA, additional, Listunov, Dymytrii, additional, Rullière, Pauline, additional, Barthes, Cécile, additional, Noirot, Céline, additional, Izquierdo, Jean-Baptiste, additional, Rozié, Alexandrine, additional, Pradines, Karen, additional, Hee, Romain, additional, de Brito, Maria Vieira, additional, Marcellin, Marlène, additional, Serre, Remy-Felix, additional, Bouchez, Olivier, additional, Burlet-Schiltz, Odile, additional, Oliveira, Maria Conceição Ferreira, additional, Ballereau, Stéphanie, additional, Bernardes-Génisson, Vania, additional, Maraval, Valérie, additional, Calsou, Patrick, additional, Hacker, Stephan M, additional, Génisson, Yves, additional, Chauvin, Remi, additional, and Britton, Sébastien, additional

Published
2022
Full Text
View/download PDF

23. Isotopically Labeled Desthiobiotin Azide (isoDTB) Tags Enable Global Profiling of the Bacterial Cysteinome

Author

Zanon, Patrick R. A., Lewald, Lisa, and Hacker, Stephan M.

Subjects
Azides, Staphylococcus aureus, Druggability, Biotin, Context (language use), Computational biology, 010402 general chemistry, Proteomics, 01 natural sciences, antibiotics, Catalysis, chemistry.chemical_compound, proteomics, Functional importance, Cysteine, Binding site, isotopic labeling, Research Articles, Molecular Structure, ATP synthase, biology, 010405 organic chemistry, Chemistry, General Medicine, General Chemistry, Protein Modifications, 0104 chemical sciences, Biochemistry, Covalent bond, Isotope Labeling, biology.protein, covalent inhibitors, Mevalonate pathway, Azide, Research Article
Abstract

Rapid development of bacterial resistance has led to an urgent need to find new druggable targets for antibiotics. In this context, residue‐specific chemoproteomic approaches enable proteome‐wide identification of binding sites for covalent inhibitors. Described here are easily synthesized isotopically labeled desthiobiotin azide (isoDTB) tags that shortened the chemoproteomic workflow and allowed an increased coverage of cysteines in bacterial systems. They were used to quantify 59 % of all cysteines in essential proteins in Staphylococcus aureus and enabled the discovery of 88 cysteines that showed high reactivity, which correlates with functional importance. Furthermore, 268 cysteines that are engaged by covalent ligands were identified. Inhibition of HMG‐CoA synthase was verified and will allow addressing the bacterial mevalonate pathway through a new target. Overall, a broad map of the bacterial cysteinome was obtained, which will facilitate the development of antibiotics with novel modes‐of‐action., On target: Isotopically labeled desthiobiotin azide (isoDTB) tags were synthesized in a straightforward manner and allowed residue‐specific profiling of the cysteinome in S. aureus. In this way, 268 cysteines that can be engaged by covalent ligands were identified. These cysteines are targets for the development of antibiotics with novel modes‐of‐action.

Published
2020

24. The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21

Author

Svenningsen, Esben B., primary, Ottosen, Rasmus N., additional, Jørgensen, Katrine H., additional, Nisavic, Marija, additional, Larsen, Camilla K., additional, Hansen, Bente K., additional, Wang, Yong, additional, Lindorff-Larsen, Kresten, additional, Tørring, Thomas, additional, Hacker, Stephan M., additional, Palmfeldt, Johan, additional, and Poulsen, Thomas B., additional

Published
2022
Full Text
View/download PDF

25. SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

Author

Demange, Pascal, primary, Joly, Etienne, additional, Marcoux, Julien, additional, Zanon, Patrick R. A., additional, Listunov, Dymytrii, additional, Rullière, Pauline, additional, Barthes, Cécile, additional, Noirot, Céline, additional, Izquierdo, Jean-Baptiste, additional, Pradines, Karen, additional, Hee, Romain, additional, de Brito, Maria Vieira, additional, Marcellin, Marlène, additional, Serre, Rémi-Félix, additional, Bouchez, Olivier, additional, Burlet-Schiltz, Odile, additional, Oliveira, Maria Conceição Ferreira, additional, Ballereau, Stéphanie, additional, Bernardes-Génisson, Vania, additional, Maraval, Valérie, additional, Calsou, Patrick, additional, Hacker, Stephan M., additional, Génisson, Yves, additional, Chauvin, Remi, additional, and Britton, Sébastien, additional

Published
2021
Full Text
View/download PDF

26. Profiling the proteome-wide selectivity of diverse electrophiles

Author

Zanon, Patrick R. A., primary, Yu, Fengchao, additional, Musacchio, Patricia, additional, Lewald, Lisa, additional, Zollo, Michael, additional, Krauskopf, Kristina, additional, Mrdović, Dario, additional, Raunft, Patrick, additional, Maher, Thomas E., additional, Cigler, Marko, additional, Chang, Christopher, additional, Lang, Kathrin, additional, Toste, F. Dean, additional, Nesvizhskii, Alexey I., additional, and Hacker, Stephan M., additional

Published
2021
Full Text
View/download PDF

28. Development of electrophiles and chemoproteomic methods for the exploration of the ligandability of bacterial proteomes

Author

Lang, Kathrin (Prof. Dr.), Zeymer, Cathleen (Prof. Dr.), Hacker, Stephan M. (Dr.), Zanon, Patrick R. A., Lang, Kathrin (Prof. Dr.), Zeymer, Cathleen (Prof. Dr.), Hacker, Stephan M. (Dr.), and Zanon, Patrick R. A.

Abstract

The herein developed chemoproteomic isoDTB-ABPP platform streamlines the identification of binding sites of covalent ligands across bacterial proteomes, providing starting points for the development of novel antibiotics. Moreover, the described advances in the profiling of nucleophilic amino acids other than cysteine will help to expand the target space of covalent ligands and thus foster the development of antibiotics with new modes-of-action., Die hier entwickelte chemoproteomische isoDTB-ABPP-Plattform ermöglicht die proteomweite Identifizierung von Bindestellen kovalenter Liganden und liefert so Ansatzpunkte für die Entwicklung neuartiger Antibiotika. Zudem werden die beschriebenen Fortschritte in der Untersuchung anderer nukleophiler Aminosäuren als Cystein dazu beitragen, die Anzahl potentieller Zielstrukturen kovalenter Liganden zu erhöhen und so die Entwicklung von Antibiotika mit neuartigen Wirkmechanismen fördern.

Published
2021

30. Competitive profiling of ligandable cysteines in Staphylococcus aureus with an organogold compound.

Author

Schmidt, Claudia, Zollo, Michael, Bonsignore, Riccardo, Casini, Angela, and Hacker, Stephan M.

Subjects
ORGANOMETALLIC compounds, BACTERIAL proteins, MASS spectrometry, ARYLATION, METALS, CYSTEINE
Abstract

With the idea of exploiting metal templated C–S bond forming reactions to achieve modification of cysteines in bacterial proteins, a cyclometalated Au(III) compound was explored in a competitive chemoproteomic approach in S. aureus cell extracts. More than 100 ligandable cysteines were identified, of which more than 50% were not engaged by organic α-chloroacetamides in a previous study, indicating that organometallic compounds expand the ligandable space in bacteria. A selected interaction was validated using an enzyme activity assay, and intact protein mass spectrometry showed cysteine arylation of an unprecedented target. The obtained results demonstrate that this family of organogold compounds has potential for therapeutic protein targeting via selective, covalent modification of cysteine residues in bacteria. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

34. Eukaryotic catecholamine hormones influence the chemotactic control of Vibrio campbellii by binding to the coupling protein CheW.

Author

Muñoz, Angela Weigert, Hoyer, Elisabeth, Schumacher, Kilian, Grognot, Marianne, Taute, Katja M., Hacker, Stephan M., Sieber, Stephan A., and Jung, Kirsten

Subjects
PROTEIN binding, ADRENERGIC agonists, CARRIER proteins, VIBRIO, HORMONES, COMMERCIAL products
Abstract

In addition to their well-known role as stress-associated catecholamine hormones in animals and humans, epinephrine (EPI) and norepinephrine (NE) act as interkingdom signals between eukaryotic hosts and bacteria. However, the molecular basis of their effects on bacteria is not well understood. In initial phenotypic studies utilizing Vibrio campbellii as a model organism, we characterized the bipartite mode of action of catecholamines, which consists of promotion of growth under iron limitation and enhanced colony expansion on soft agar. In order to identify the molecular targets of the hormones, we designed and synthesized tailored probes for chemical proteomic studies. As the catechol group in EPI and NE acts as an iron chelator and is prone to form a reactive quinone moiety, we devised a photoprobe based on the adrenergic agonist phenylephrine (PE), which solely influenced colony expansion. Using this probe, we identified CheW, located at the core of the chemotaxis signaling network, as a major target. In vitro studies confirmed that EPI, NE, PE, and labetalol, a clinically applied antagonist, bind to purified CheW with affinity constants in the submicromolar range. In line with these findings, exposure of V. campbellii to these adrenergic agonists affects the chemotactic control of the bacterium. This study highlights an effect of eukaryotic signaling molecules on bacterial motility. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

38. Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms

Author

Le, Philipp, primary, Kunold, Elena, additional, Macsics, Robert, additional, Rox, Katharina, additional, Jennings, Megan C., additional, Ugur, Ilke, additional, Reinecke, Maria, additional, Chaves-Moreno, Diego, additional, Hackl, Mathias W., additional, Fetzer, Christian, additional, Mandl, Franziska A. M., additional, Lehmann, Johannes, additional, Korotkov, Vadim S., additional, Hacker, Stephan M., additional, Kuster, Bernhard, additional, Antes, Iris, additional, Pieper, Dietmar H., additional, Rohde, Manfred, additional, Wuest, William M., additional, Medina, Eva, additional, and Sieber, Stephan A., additional

Published
2019
Full Text
View/download PDF

40. Neocarzilin A Is a Potent Inhibitor of Cancer Cell Motility Targeting VAT-1 Controlled Pathways

Author

Gleissner, Carolin M.-L., primary, Pyka, Carolin L., additional, Heydenreuter, Wolfgang, additional, Gronauer, Thomas F., additional, Atzberger, Carina, additional, Korotkov, Vadim S., additional, Cheng, Weiting, additional, Hacker, Stephan M., additional, Vollmar, Angelika M., additional, Braig, Simone, additional, and Sieber, Stephan A., additional

Published
2019
Full Text
View/download PDF

42. Broad Spectrum Antibiotic Xanthocillin X Effectively Kills Acinetobacter baumanniiviaDysregulation of Heme Biosynthesis

Author

Hübner, Ines, Shapiro, Justin A., Hoßmann, Jörn, Drechsel, Jonas, Hacker, Stephan M., Rather, Philip N., Pieper, Dietmar H., Wuest, William M., and Sieber, Stephan A.

Abstract

Isonitrile natural products exhibit promising antibacterial activities. However, their mechanism of action (MoA) remains largely unknown. Based on the nanomolar potency of xanthocillin X (Xan) against diverse difficult-to-treat Gram-negative bacteria, including the critical priority pathogen Acinetobacter baumannii, we performed in-depth studies to decipher its MoA. While neither metal binding nor cellular protein targets were detected as relevant for Xan’s antibiotic effects, sequencing of resistant strains revealed a conserved mutation in the heme biosynthesis enzyme porphobilinogen synthase (PbgS). This mutation caused impaired enzymatic efficiency indicative of reduced heme production. This discovery led to the validation of an untapped mechanism, by which direct heme sequestration of Xanprevents its binding into cognate enzyme pockets resulting in uncontrolled cofactor biosynthesis, accumulation of porphyrins, and corresponding stress with deleterious effects for bacterial viability. Thus, Xanrepresents a promising antibiotic displaying activity even against multidrug resistant strains, while exhibiting low toxicity to human cells.

Published
2021
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results