Project Cluster 2: Natural product/HDAC inhibitor-mediated modulation of immune responses and cytostatic-induced stress responses for resensitization of therapy-resistant tumors
The research program comprehends 4 different, but strongly interconnected project fields. Collectively, these fields cover all important aspects of preclinical research of active agents starting from the discovery of active agents, characterization of the molecular targets and mechanism of action and modulation of immune system, leading to a directed medical chemical substance optimization supported by in silico processes.
Please find all project descriptions with the specific requirements below. Please be aware that you have to choose at least one project (see Instructions for application).
Click on the project to find more information.
Supervisor: Prof. Dr. Stefanie Scheu, Institute of Medical Microbiology and Hospital Hygiene
The development of resistances against cytostatic drugs or antibiotics is currently a major challenge in the treatment of cancer and infectious diseases. Combining a direct tumoricidal or bactericidal activity with an immunomodulatory effect within one and the same substance may synergistically counteract the development of resistance. Using a specifically designed screening pipeline to identify new lead structures, a library of natural product isolates and natural product-derived histone deacetylase inhibitors (HDACis) has been screened for a capacity to activate intrinsic effector functions of primary murine antigen-presenting cells and compared with screening results from other GRK projects with respect to direct antitumor and antipathogenic properties. Several polypharmacological compounds have been identified that are able to activate or potentiate type I interferon and IL-12 production as well the antigen-presenting capacity of dendritic cells while having a direct toxic effect on tumor cells. The goal of this project is to characterize the molecular mechanisms underlying the immunomodulatory capabilities of the respective compounds. From the identified immune-activating natural products or HDACis, exact lead structures will be derived and functionally modified after successful target discovery in close collaboration with other labs of the Research Training Group.
The ideal candidate will have a record of excellence and a strong background in immunology/cellular biology or molecular biology and biochemistry.
- Yang, X. et al. The mycotoxin Beauvericin exhibits immunostimulatory effects on dendritic cells via activating the TLR4 signaling pathway. Front Immunol, accepted for publication, bioRxiv: 2022.2001.2020.476919 (2022).
- Salmon, J. et al. Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML. Cancer Discov doi: 10.1158/2159-8290.CD-20-1145. Epub ahead of print (2022).
- Richter, L., Kropp, S., Proksch, P. & Scheu, S. A mouse model-based screening platform for the identification of immune activating compounds such as natural products for novel cancer immunotherapies. Bioorg Med Chem 27, 115145 (2019).
- Bauer, J. et al. Cutting Edge: IFN-beta Expression in the Spleen Is Restricted to a Subpopulation of Plasmacytoid Dendritic Cells Exhibiting a Specific Immune Modulatory Transcriptome Signature. J Immunol 196, 4447-4451 (2016).
Project Cluster 4: Nisin as a model system to overcome lantibiotic resistance in bacterial pathogens
Supervisor: Prof. Dr. Holger Gohlke, Institute of Pharmaceutical and Medicinal Chemistry
Nisin is a bactericidal peptide produced by certain Gram-positive bacteria, such as Lactococcus spp., the best-studied lantibiotic, and, as such, a model system to understand and overcome lantibiotic resistance in bacterial pathogens. Lantibiotic resistance often occurs in human pathogenic bacterial strains (including Streptococcus agalactiae) that do not produce nisin themselves. Resistance is mediated by the operon-encoded proteins NSR, a serine protease, NsrFP, an ABC transporter, and NsrRK, a two-component system. Furthermore, to gain immunity against nisin, the producing Lactococcus spp. expresses, among other proteins, the ABC transporter NisFEG.
In previous work and applying integrative modeling in tight collaboration with experimental groups of the GRK, we succeeded in generating a model of the SaNSR/nisin complex,(1, 2) identified the first small-molecule inhibitors of SaNSR by virtual screening (3) and performed initial lead optimization, as well as characterized the nucleotide-binding domain SaNsrF.(4) In so far unpublished work, we generated structural models of SaNsrP and NisEG, using ab initio modeling, coevolutionary information, and experimental data, as a basis to scrutinize their molecular functions.
The overarching goal of the upcoming PhD project is to overcome lantibiotic resistance, specifically nisin resistance, in bacterial pathogens by means of structural and mechanistic approaches. Here, computer-assisted molecular modeling and simulation approaches performed in our group will be closely interlinked with biochemical/structural biological (performed in the group of Prof. S. Smits) and medicinal chemistry (performed in the group of Prof. H. Stark) work, as has been successfully applied up to now. Specifically, we will optimize small-molecule inhibitors of SaNSR and elucidate the molecular mechanisms of NsrFP and NisFEG.
Ideal candidates will have a record of excellence and a strong background in computational biochemistry/chemistry or structural bioinformatics, a high interest in working in an interdisciplinary collaboration, and profound knowledge in state-of-the-art molecular dynamics simulations (Amber) software, molecular modeling (including protein-ligand and protein-protein-complex structure predictions and evaluations), and medicinal chemistry.
- Khosa S, Frieg B, Mulnaes D, Kleinschrodt D, Hoeppner A, Gohlke H, et al. Structural basis of lantibiotic recognition by the nisin resistance protein from Streptococcus agalactiae. Sci Rep. 2016;6:18679.
- Mulnaes D, Porta N, Clemens R, Apanasenko I, Reiners J, Gremer L, et al. TopModel: Template-Based Protein Structure Prediction at Low Sequence Identity Using Top-Down Consensus and Deep Neural Networks. J Chem Theory Comput. 2020;16(3):1953-67.
- Porta N, Zaschke-Kriesche J, Frieg B, Gopalswamy M, Zivkovic A, Etzkorn M, et al. Small-molecule inhibitors of nisin resistance protein NSR from the human pathogen Streptococcus agalactiae. Bioorg Med Chem. 2019;27:115079.
- Furtmann F, Porta N, Hoang DT, Reiners J, Schumacher J, Gottstein J, et al. Characterization of the nucleotide-binding domain NsrF from the BceAB-type ABC-transporter NsrFP from the human pathogen Streptococcus agalactiae. Sci Rep. 2020;10(1):15208.