Working Group Kalscheuer
News
Research stay of a guest scientist from Cameroon
07 Jan 2025
Dr. Joseph Tchamgoue from the Department of Organic Chemistry, Faculty of Science, University of Yaounde (Cameroon) is visiting the Kalscheuer group for a period of three months, funded by the TWAS-DFG Cooperation Visits Programme for Postdoctoral researchers from Sub-Saharan Africa. Dr. Joseph Tchamgoue will work on bioprospecting of selected basidiomycetes for the production of novel antimicrobial and antiparasitic natural products.
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Media reports on the research activities of the Kalscheuer group
23 September 2024
The Rheinische Post and the WDR Lokalzeit Düsseldorf (from minute 3:58 in the linked video) reported on the research of the Kalscheuer group on the development of novel antibacterial substances against the tuberculosis pathogen Mycobacterium tuberculosis.
Publication in Cell Chemical Biology - New principle for treating tuberculosis
26 July 2024
Researchers from Heinrich Heine University Düsseldorf (HHU) and the University of Duisburg-Essen (UDE) have together succeeded in identifying and synthesising a group of molecules that can act against the cause of tuberculosis in a new way. In the scientific journal Cell Chemical Biology, they describe that the so-called callyaerins act against the infectious disease employing a fundamentally different mechanism compared to antibiotic agents used to date.
The infectious disease tuberculosis is caused by the bacterium Mycobacterium tuberculosis (for short: M. tuberculosis). More than ten million people contract the disease worldwide every year. According to the World Health Organisation (WHO), 1.6 million people died of tuberculosis in 2021 alone. This makes it one of the most significant infectious diseases and, in particular in countries with inadequate healthcare systems, it represents a serious threat to the population.
Over time, M. tuberculosis has developed resistance to many antibiotics, making treatment increasingly difficult. There are currently only a few drugs available that are effective against resistant strains. Researchers are therefore seeking new antibacterial compounds and mechanisms of action as a basis for the development of completely new drugs.
A research team headed by Professor Dr Rainer Kalscheuer from the Institute of Pharmaceutical Biology and Biotechnology at HHU and Professor Dr Markus Kaiser from the Center of Medical Biotechnology at UDE has identified one such fundamentally new approach involving callyaerins. Chemically, these natural substances of marine origin are classed as so-called cyclopeptides.
“We have succeeded in chemically synthesising the substance that occurs naturally in marine sponges in order to test its effect on tuberculosis bacteria in cell cultures. This has enabled us to produce new, more potent derivatives that do not exist in nature. Such chemical synthesis needs to be successful before a potential active agent can be used as a drug on a large scale,” explains Dr David Podlesainski from UDE, one of the two lead authors of the study that has now been published in Cell Chemical Biology.
The tuberculosis bacterium primarily infects human phagocytes, the so-called macrophages, in which the bacteria then multiply. The researchers have now discovered that callyaerins can inhibit the growth of the bacterium in human cells.
Emmanuel Tola Adeniyi, doctoral researcher at HHU and co-lead author of the study: “The callyaerins attack a specific membrane protein of M. tuberculosis called Rv2113, which is not essential for the viability of the bacterium. This comprehensively disrupts the metabolism of the bacterium, hindering its growth. By contrast, human cells remain unaffected by the callyaerins.”
Professor Kalscheuer, corresponding author of the study: “With the callyaerins, we have discovered a new mechanism of action. Unlike other antibiotics, these substances do not block vital metabolic pathways in the bacterial cell. Instead, they directly attack a non-essential membrane protein of the bacterium, which has not been considered as a potential target before.”
Professor Kaiser, the second corresponding author, focuses on a further perspective: “In further research work, we now need to clarify precisely how callyaerins interact with Rv2113 and how this interaction disrupts various cellular processes in such a way that M. tuberculosis can no longer grow. However, we have been able to show that non-essential proteins can also represent valuable target structures for the development of novel antibiotics.”
Originalpublikation
David Podlesainski, Emmanuel T. Adeniyi, Yvonne Gröner, Florian Schulz, Violetta Krisilia, Nidja Rehberg, Tim Richter, Daria Sehr, Huzhuyue Xie, Viktor E. Simons, Anna-Lene Kiffe-Delf, Farnusch Kaschani, Thomas R. Ioerger, Markus Kaiser, and Rainer Kalscheuer. The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113. Cell Chemical Biology 31 (2024).
DOI: 10.1016/j.chembiol.2024.06.002
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Publication on elucidation of the antibacterial mode-of-action of nature-inspired bisindole alkaloids
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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Successful completion of the first round of the "Endophyte hunters" Citizens' University project
23 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.
Contribution of the Kalscheuer lab to a seminal study on the BacPROTAC concept published in the leading life science journal Cell
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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06.10.2022
The Kalscheuer lab congratulates Prof. Carolyn R. Bertozzi for being awarded the Nobel Prize in Chemistry 2022 "for the development of click chemistry and bioorthogonal chemistry" !
Check out our translational collaborative work with Carolyn using bioorthogonal chemistry to study and exploit trehalose metabolism in Mycobacterium tuberculosis.
