AK Kalscheuer

14.06.2024

There is a new research paper of the Kalscheuer group elucidating the antibacterial mechanism and molecular targets of synthetic nature-inspired bisindoles that exhibit potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), published in ACS Infectious Diseases (https://pubs.acs.org/doi/abs/10.1021/acsinfecdis.3c00657).  In this paper, mechanistic studies revealed that synthetic bisindoles impact the cytoplasmic membrane of Gram-positive bacteria by promiscuously interacting with lipid II and membrane phospholipids while rapidly dissipating membrane potential, providing a potential starting point for drug development in the fight against MRSA. While most pharmaceutical drugs are inhibiting protein targets, bisindole alkaloids are unusual as they interact with lipids, similar to certain antibiotics such as vancomycin. This study was conducted in close collaboration with the group of Thomas Müller (Institute of Organic Chemistry and Macromolecular Chemistry, HHU Düsseldorf) in context of the DFG Research Training Group GRK 2158 “Natural products and natural product analogs against therapy-resistant tumors and microorganisms: new lead structures and modes of action”.

Original publication:

Adeniyi ET*, Kruppa M*, De Benedetti S, Ludwig KC, Krisilia V, Wassenberg TR, Both M, Schneider T, Müller TJJ*, Kalscheuer R*. Synthesis of bisindole alkaloids and their mode of action against methicillin-resistant Staphylococcus aureus. ACS Inf. Dis 10, 1958–1969 (2024). https://doi.org/10.1021/acsinfecdis.3c00657

*These authors contributed equally. 

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23.05.2024

Im Rahmen der Bürgeruniversität haben sich in einer ersten Projektrunde acht Bürger*innen an einem Forschungsprojekt unter der Leitung von Prof. Dr. Rainer Kalscheuer beteiligt, welches vom Rektorat der HHU mit einer Sonderförderung ermöglicht wurde. An insgesamt fünf Kurstagen konnten die Bürger*innen einen hautnahen, praxisbezogenen Einblick in den wissenschaftlichen Laboralltag und die Wirkstoffforschung gewinnen und sich über die Problematik der antimikrobiellen Resistenzentwicklung informieren. Die Bürger*innen sammelten Pflanzenmaterial, aus denen sie im Labor unter der Anleitung von Prof. Dr. Rainer Kalscheuer und Dr. Lasse van Geelen endophytische Pilze isolierten. Neben der Durchführung einer Polymerasekettenreaktion und anschließender DNA-Sequenzierung zur taxonomischen Identifizierung der Pilze testeten die Bürger*innen Extrakte der Pilze auf antibakterielle Aktivität. Die endophytischen Pilze werden in der Arbeitsgruppe Kalscheuer nun weiter auf ihrer antibakteriellen Inhaltsstoffe hin untersucht. Somit unterstützen die engagierten Bürger*innen nicht nur langfristig die Forschungsaktivitäten der Arbeitsgruppe Kalscheuer, sondern könnten zukünftig vielleicht sogar selber einen handfesten praktischen Beitrag zur Entwicklung neuer, dringend benötigter Wirkstoffe geleistet haben. Weitere Informationen zu unserem Bürgeruni-Projekt „Endophytenjäger“ finden sie unter diesem Link.

24.04.2024

See our recent contribution to an invited review article entitled “Architecture, function, regulation and evolution of α-glucans metabolic enzymes in prokaryotes” published in Chemical Reviews, which is one of the highest-ranked journals covering general topics of chemistry (IF 62.1). This review was written by Rainer Kalscheuer in collaboration  with colleagues from the University of the Basque Country, the Molecular Biology Institute of Barcelona (IBMB), and the University of Lille.

Original publication:

Cifuente JO, Colleoni C, Kalscheuer R, Guerin ME. Architecture, Function, Regulation, and Evolution of α-Glucans Metabolic Enzymes in Prokaryotes. Chem Rev. (2024) online ahead of print  (doi: 10.1021/acs.chemrev.3c00811).

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05.03.2024

See our recent contribution to a study advancing the homo-BacPROTAC concept as new antimybacterial treatment option published in Nature Communications. This study was conducted in collaboration with Guido Boehmelt and coworkers at Boehringer Ingelheim RCV, Vienna, Austria, Lukas Junk at Saarland University, and further colleagues.

Homo-BacPROTACs consist of two cyclomarin A-molecules, which both can bind separate ClpC1 proteins. ClpC1 represents the mycobacterial ATP-driven unfoldase of the quasi-proteasomal like ClpC:ClpP (ClpCP) protease. Homo-BacPROTACs induce proximity between separate ClpC1 proteins, which results in selfdegradation of ClpC1 and impairs activity of the Clp protein quality control system. This innovative technology may provide a new way to tackle the rising problem of antimicrobial resistance in the human pathogen Mycobacterium tuberculosis.

Original publication:

Junk L*, Schmiedel VM*, Guha S, Fischel K, Greb P, Vill K, Krisilia V, van Geelen L, Rumpel K, Kaur P, Krishnamurthy RV, Narayanan S, Shandil RK, Singh M, Kofink C, Mantoulidis A, Biber P, Gmaschitz G, Kazmaier U, Meinhart A, Leodolter J, Hoi D, Junker S, Morreale FE, Clausen T, Kalscheuer R, Weinstabl H, Boehmelt G. Homo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria. Nat Commun 15, 2005 (2024). https://doi.org/10.1038/s41467-024-46218-7

*These authors contributed equally. 

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03.05.2023

The Kalscheuer lab is pleased to share a contribution to a seminal study reporting on development of the BacPROTAC concept as a new antimycobacterial treatment option published in the leading life science journal Cell (IF 66.85). This study was conducted in collaboration with Tim Clausen´s lab at the Vienna BioCenter, Lukas Junk at Saarland University, and further collaegues.

Mycobacterium tuberculosis, the causative agent of tuberculosis, was the second leading cause of death by a single pathogen after SARS-CoV-2 in 2021. Although the Corona pandemic has been overcome, tuberculosis remains a major global health burden. Discovering new effective drugs to tackle the increasing problem of emerging multi-drug resistant tuberculosis proves to be difficult due to the high intrinsic resistance of M. tuberculosis.

A promising drug target is the Clp system in M. tuberculosis, which is essential to eliminate misfolded and futile proteins. An increase or decrease in the Clp activity could lead to an imbalance of protein synthesis and salvage ultimately resulting in cell death. The natural products cyclomarin A and ecumicin can bind to one crucial component of the Clp system, the unfoldase ClpC1, which prevents ClpC1 to interact normally with misfolded or futile proteins. As a result, the Clp system transitions into hyperactivity and therefore degrades nearby proteins, which might be important for cell survival. However, the bacterial defence towards cyclomarin A and ecumicin reacts in upregulation of another Clp protein, ClpC2. This protein protects the ClpC1 protein from binding cyclomarin A and ecumicin and decreases the efficiency of the drugs.

Homo-BacPROTACs, which have been designed and evaluated in this study, consist of two cyclomarin A-molecules, which both can bind separate ClpC1 proteins. Binding two different ClpC1 proteins brings them in close proximity to one another resulting in degradation and impaired activity of the Clp system. Additionally, the Homo-BacPROTACs also target ClpC2 and thereby circumvent the resistance mechanism. The BacPROTAC system can be altered and adapted to target other proteins and selectively degrade these proteins facilitating the Clp system. This highly adaptive and innovative technology provides a new way to tackle the rising problem of antimicrobial resistance in M. tuberculosis.

Original publication:

David M. Hoi*, Sabryna Junker*, Lukas Junk, Kristin Schwechel, Katharina Fischel, David Podlesainski, Paige M. E. Hawkins, Lasse van Geelen, Farnusch Kaschani, Julia Leodolter, Francesca Ester Morreale, Stefan Kleine, Somraj Guha, Klaus Rumpel, Volker M. Schmiedel, Harald Weinstabl, Anton Meinhart, Richard J. Payne, Markus Kaiser, Markus Hartl, Guido Boehmelt, Uli Kazmaier, Rainer Kalscheuer, Tim Clausen: “Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival”. Cell (2023), DOI: 10.1016/j.cell.2023.04.009. 
*These authors contributed equally. 

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