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Your search keyword '"Hackl, Mathias W."' showing total 14 results
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14 results on '"Hackl, Mathias W."'

2. 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
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5. Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers

Author

Messner, Martina, Mandl, Melanie M., Hackl, Mathias W., Reinhardt, Till, Ardelt, Maximilian A., Szczepanowska, Karolina, Fraedrich, Julian E., Waschke, Jens, Jeremias, Irmela, Fux, Anja, Stahl, Matthias, Vollmar, Angelika M., Sieber, Stephan A., Pachmayr, Johanna, Messner, Martina, Mandl, Melanie M., Hackl, Mathias W., Reinhardt, Till, Ardelt, Maximilian A., Szczepanowska, Karolina, Fraedrich, Julian E., Waschke, Jens, Jeremias, Irmela, Fux, Anja, Stahl, Matthias, Vollmar, Angelika M., Sieber, Stephan A., and Pachmayr, Johanna

Abstract

The human mitochondrial ClpXP protease complex (HsClpXP) has recently attracted major attention as a target for novel anti-cancer therapies. Despite its important role in disease progression, the cellular role of HsClpXP is poorly characterized and only few small molecule inhibitors have been reported. Herein, we screened previously established S. aureus ClpXP inhibitors against the related human protease complex and identified potent small molecules against human ClpXP. The hit compounds showed anti-cancer activity in a panoply of leukemia, liver and breast cancer cell lines. We found that the bacterial ClpXP inhibitor 334 impairs the electron transport chain (ETC), enhances the production of mitochondrial reactive oxygen species (mtROS) and thereby promotes protein carbonylation, aberrant proteostasis and apoptosis. In addition, 334 induces cell death in re-isolated patient-derived xenograft (PDX) leukemia cells, potentiates the effect of DNA-damaging cytostatics and re-sensitizes resistant cancers to chemotherapy in non-apoptotic doses.

Published
2021

8. 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
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10. Comparative Target Analysis of Chlorinated Biphenyl Antimicrobials Highlights MenG as Molecular Target of Triclocarban.

Author

Macsics, Robert, Hackl, Mathias W., Fetzer, Christian, Mostert, Dietrich, Bender, Jennifer, Layer, Franziska, and Sieber, Stephan A.

Subjects
*SMALL molecules, *ARGININE deiminase, *BACTERIAL metabolism, *ANTI-infective agents, *ENERGY metabolism, *TRICLOCARBAN, *TRICLOSAN, *DIARYL compounds
Abstract

Triclocarban (TCC), a formerly used disinfectant, kills bacteria via an unknown mechanism of action. A structural hallmark is its N,N'-diaryl urea motif which is also present in other antibiotics including the recently reported small molecule PK150. We here show that, like PK150, TCC exhibits an inhibitory effect on Staphylococcus aureus menaquinone metabolism via inhibition of the biosynthesis protein MenG. However, the activity spectrum (MIC90) of TCC across a broad range of multi-drug resistant staphylococci and enterococci strains was much narrower compared to PK150. Accordingly, TCC did not cause an over-activation of signal peptidase SpsB, a hallmark of the PK150 mode of action. Furthermore, we were able to rule out inhibition of FabI, a confirmed target of the diaryl ether antibiotic triclosan (TCS). Differences in the target profile of TCC and TCS were further investigated by proteomic analysis, showing complex, but rather distinct changes in the protein expression profile of S. aureus. Downregulation of the arginine deiminase pathway provided additional evidence for an effect on bacterial energy metabolism by TCC. [ABSTRACT FROM AUTHOR]

Published
2020
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12. Reversible Inhibitoren arretieren ClpP in einer definierten Konformation, die durch Bindung von ClpX aufgehoben wird

Author

Pahl, Axel, primary, Lakemeyer, Markus, additional, Vielberg, Marie‐Theres, additional, Hackl, Mathias W., additional, Vomacka, Jan, additional, Korotkov, Vadim S., additional, Stein, Martin L., additional, Fetzer, Christian, additional, Lorenz‐Baath, Katrin, additional, Richter, Klaus, additional, Waldmann, Herbert, additional, Groll, Michael, additional, and Sieber, Stephan A., additional

Published
2015
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13. Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association

Author

Pahl, Axel, primary, Lakemeyer, Markus, additional, Vielberg, Marie‐Theres, additional, Hackl, Mathias W., additional, Vomacka, Jan, additional, Korotkov, Vadim S., additional, Stein, Martin L., additional, Fetzer, Christian, additional, Lorenz‐Baath, Katrin, additional, Richter, Klaus, additional, Waldmann, Herbert, additional, Groll, Michael, additional, and Sieber, Stephan A., additional

Published
2015
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14. Phenyl Esters Are Potent Inhibitors of Caseinolytic Protease P and Reveal a Stereogenic Switch for Deoligomerization

Author

Hackl, Mathias W., primary, Lakemeyer, Markus, additional, Dahmen, Maria, additional, Glaser, Manuel, additional, Pahl, Axel, additional, Lorenz-Baath, Katrin, additional, Menzel, Thomas, additional, Sievers, Sonja, additional, Böttcher, Thomas, additional, Antes, Iris, additional, Waldmann, Herbert, additional, and Sieber, Stephan A., additional

Published
2015
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