Members

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)

Müller Lab

An institution of the Helmholtz Centre for Infection Research in cooperation with Saarland UniversityCoordinator Novel Antibiotics, German Centre for Infection Research (DZIF)

Representative

Prof. Dr. Rolf Müller- Managing Director and Head of Department Microbial Natural Products

Team

  • Prof. Dr. Uli Kazmaier
  • Prof. Dr. Anna K. H. Hirsch
  • Dr. Jennifer Herrmann
  • Dr. Sari Rasheed
  • Dr. Andreas Kany

About

Helmholtz Institute for Pharmaceutical Research Saarland:

The Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) in Saarbrücken was founded jointly by the Helmholtz Centre for Infection Research (HZI) and Saarland University in 2009. Scientists at HIPS develop and employ experimental and computational approaches to provide new active substances against infectious diseases, optimise them for use in humans and investigate how they can best be transported to their site of action in the human body. A special focus of the institute is on microbial natural products from soil bacteria and the human microbiota as well as innovative medicinal chemistry-driven approaches. www.helmholtz-hips.de

Helmholtz Centre for Infection Research:

Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and other locations in Germany study bacterial and viral infections and the body’s defence mechanisms. They have in-depth expertise in natural product research and its use as a valuable source for novel anti-infectives. As a member of the Helmholtz Association and the German Centre for Infection Research (DZIF), the HZI conducts translational research to lay the foundations for the development of novel therapies and vaccines against infectious diseases. www.helmholtz-hzi.de

Role & Expertise:

The Helmholtz Centre for Infection Research (HZI) and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) have world leading capabilities in identifying and exploiting natural products for drug discovery. 

Aiming to fill the gap in the TB drug discovery and development pipeline, novel natural products (NPs) and already confirmed hits will be studied to identify potent antitubercular molecules with new mechanisms of action (MoA) that address either entirely novel targets or bind to known targets, thereby overcoming resistance in Mtb. For this, we will build on the existing projects to identify novel compounds as leads and potentially candidates for clinical evaluation in TB and follow different approaches to make these NPs accessible for lead optimization (LO). HIPS/HZI will contribute to the TBDA by carrying out the NP-related work such as genome mining, bioactivity screening as well as dereplication, isolation and structure elucidation of hits, large-scale fermentation, total syntheses and analoging, as well as MoA and resistance evaluation of Hit to Lead (H2L) candidates. Additionally, scientists at HIPS have nominated several promising series and new/underexplored chemical scaffolds addressing promising targets in TB for furthers characterization. Moreover, we will continue our efforts towards finding Mtb actives to identify novel chemical entities (NCEs) from more advanced screening campaigns for future hit nomination.

Links

HIPS/MINS: https://www.helmholtz-hips.de/en/research/teams/team/microbial-natural-products/

Twitter/X: @Helmholtz_HIPS

Instagram: @helmholtz_hips_de

LinkedIn: https://www.linkedin.com/company/helmholtz-hips

References

  1. Fu, C.; Liu, Y.; Walt, C.; Rasheed, S.; Bader, C.D.; Lukat, P.; Neuber, M.; Haeckl, F.P.J.; Blankenfeldt, W.; Kalinina, O.V.; Müller, R. (2024) Elucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis antibiotics Mycoplanecins. Nat. Commun.; 2024, 15, 791, doi.org/10.1038/s41467-024-44953-5
  2. Couturier, C.; Groß, S.; Tesmar, A.; Hoffmann, J.; Deckarm, S.; Fievet, A.; Dubarry, N.; Taillier, T.; Pöverlein, C.; Stump, H.; Kurz, M.; Toti, L.; Haag Richter, S.; Schummer, D.; Sizun, P.; Hoffmann, M.; Prasad Awal, R.; Zaburannyi, N.; Harmrolfs, K.; Wink, J.; Lessoud, E.; Vermat, T.; Cazals, V.; Silve, S.; Bauer, A.; Mourez, M.; Fraisse, L.; Leroi-Geissler, C.; Rey, A.; Versluys, S.; Bacqué, E.; Müller, R.; Renard, S. Structure Elucidation, Total Synthesis, Antibacterial In Vivo Efficacy and Biosynthesis Proposal of Myxobacterial Corramycin. Angew. Chem.Int. Ed.; 2022, 61:e202210747. doi: 10.1002/anie.202210747
  3. Koller, T.O.; Scheid, U.; Kösel, T.; Herrmann, J.; Krug, D.; Boshoff, H.I.M.; Beckert, B.; Evans, J.C.; Schlemmer, J.; Sloan, B.; Weiner, D.M.; Via, L.E.; Moosa, A.; Ioerger, T.R.; Graf, M.; Zinshteyn, B.; Abdelshahid, M.; Nguyen, F.; Arenz, S.; Gille, F.; Siebke, M.; Seedorf, T.; Plettenburg, O.; Green, R.; Warnke, A-L.; Ullrich, J.; Warrass, R.; Barry 3rd, C.E.; Warner, D.F.; Mizrahi, V.; Kirschning, A.; Wilson, D.A.; and Müller, R. The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition. J. Am. Chem. Soc. 2023, 145, 2, 851–863. doi: 10.1021/jacs.2c08816
  4. Seyfert, C.; Porten, P.; Yuan, B.; Deckarm, S.; Panter, P.; Bader, P.; Coetzee, J.; Deschner, F.; Tehrani, K.; Higgins, P.; Seifert, H.; Marlovits, T.; Herrmann, J.; Müller, R. Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering. Angew. Chem. Int. Ed.; 2022, 62(2):e202214094. https://doi.org/10.1002/anie.202214094
  5. Hofer, W.; Oueis, E.; Abou Fayad, A.; Deschner, F.; Andreas, A.; Pessanha de Carvalho, L.; Hüttel, S.; Bernecker, S.; Pätzold, L.; Morgenstern, B.; Zaburannyi, N.; Bischoff, M.; Stadler, M.; Held, J.; Herrmann, J.; Müller, R. Regio- and stereoselective epoxidation and acidic epoxide opening of antibacterial and antiplasmodial chlorotonils yield highly potent derivatives. Angew. Chem. Int. Ed.; 2022, 61: e202202816. doi: 10.1002/anie.202202816
  6. Hoffmann, T.; Krug, D.; Bozkurt, N.; Duddela, S.; Jansen, R. Garcia, R.; Gerth, K.; Steinmetz, H. and Müller, R. (2018) Correlating chemical diversity with taxonomic distance for discovery of natural products in myxobacteria. Nat. Commun.; 9 (1): 803. doi: 10.1038/s41467-018-03184-1
  7. Hüttel, S.; Giambattista, T.; Herrmann, J.; Planke, T.; Gille, F.; Moreno, M.; Stadler, M.; Brönstrup, M.; Kirschning, A. and Müller, R. Discovery and total synthesis of natural cystobactamid derivatives with superior activity against Gram-negative pathogens. Angew. Chem. Int. Ed.; 2017, 56 (41): 12760-64. https://doi.org/10.1002/anie.201705913
  8. Kling, A.; Lukat, P.; Almeida, D.V.; Bauer, A.; Fontaine, E, Sordello, S.; Zaburannyi, N.; Herrmann, J.; Wenzel, S.C.; König, C.; Ammerman, N.C.; Barrio, M.B.; Borchers, K.; Bordon-Pallier, F.; Brönstrup, M.; Courtemanche, G.; Gerlitz, M.; Geslin, M.; Hammann, P.; Heinz, D.W.; Hoffmann, H.; Klieber, S.; Kohlmann, M.; Kurz, M.; Lair, C.; Matter, H.; Nuermberger, E.; Sandeep T.; Fraisse, L.; Grosset, J.H.; Lagrange, S. and Müller, R. Targeting DnaN for tuberculosis therapy using novel griselimycins. Science, 2015, 348 (6239): 1106-12. doi: 10.1126/science.aaa4690
  9. Fu, J.; Bian, X.; Hu, S.; Wang, H.; Huang, F.; Seibert, P.M.; Plaza, A.; Xia, L.; Müller, R., Stewart, A.F. and Zhang, Y. Full-length RecE enhances linear-linear homologous recombination and facilitates direct cloning for bioprospecting, Nat. Biotechnol.; 2012, 30 (5): 440-446. doi: 10.1038/nbt.2183 (authors contributed equally)
  10. Schneiker, S.; Perlova, O.; Kaiser, O.; Gerth, K.; Alici, A.; Altmeyer, M.O.; Bartels, D.; Bekel, T.; Beyer, S.; Bode, E.; Bode, H.B.; Bolten, C.J.; Choudhuri, J.V.; Doss, S.; Elnakady, Y.A.; Frank, B.; Gaigalat, L.; Goesmann, A.; Groeger, C.; Gross, F.; Jelsbak, L.; Jelsbak, L.; Kalinowski, J.; Kegler, C.; Knauber, T.; Konietzny, S.; Kopp, M.; Krause, L.; Krug, D.; Linke, B.; Mahmud, T.; Martinez-Arias, R.; McHardy, A.C.; Merai, M.; Meyer, F.; Mormann, S, Muñoz-Dorado, J.; Perez, J.; Pradella, S.; Rachid, S.; Raddatz, G.; Rosenau, F.; Rückert, C.; Sasse, F.; Scharfe, M.; Schuster, S.C.; Suen, G.; Treuner-Lange, A.; Velicer, G.J.; Vorhölter, F.J.; Weissman, K.J.; Welch, R.D.; Wenzel, S.C.; Whitworth, D.E.; Wilhelm, S.; Wittmann, C.; Blöcker, H.; Pühler, A. and Müller, R. Complete genome sequence of the myxobacterium Sorangium cellulosum. Nat. Biotechnol.; 2007 25 (11): 1281-1289. doi: 10.1038/nbt1354