Working group 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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23rd May 2024

As part of the Citizens' University, eight members of the public took part in the first round of a research project led by Prof Dr Rainer Kalscheuer, which was made possible by special funding from the HHU Rectorate. On a total of five course days, the citizens were able to gain a first-hand, practical insight into everyday scientific laboratory work and drug research and learn about the problem of antimicrobial resistance development. The citizens collected plant material from which they isolated endophytic fungi in the laboratory under the guidance of Prof Dr Rainer Kalscheuer and Dr Lasse van Geelen. In addition to carrying out a polymerase chain reaction and subsequent DNA sequencing for taxonomic identification of the fungi, the citizens tested extracts of the fungi for antibacterial activity. The endophytic fungi are now being further analysed for their antibacterial ingredients in the Kalscheuer working group. In this way, the committed citizens are not only supporting the research activities of the Kalscheuer working group in the long term, but may even have made a tangible practical contribution to the development of new, urgently needed active ingredients themselves in the future. Further information on our Citizens' University project "Endophyte Hunters" can be found under this link.

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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