Secondary Metabolites in Amoebae-Bacteria Interactions (SMABI)

• Applicant: Professor Dr. Pierre Stallforth
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388472265

• Final Report Year: 2021

Final Report Abstract

The aim of this project was to shed light on natural products within microbial predator–prey associations. In particular, we investigated natural products that occur within the association of pseudomonads and bacterivorous amoebae. We focused in the first part on the novel bacterial alkaloids, the pyreudiones. A strategic structure-activityrelationship study allowed us to identify the motifs that contribute to activity and to guide us to their mode of actions. The latter was a result of the protonophore activity of the pyreudiones. Detailed biosynthetic studies allowed us to understand how these molecules are assembled. Pyreudiones are produced by monomodular nonribosomal peptide synthetases. While these biosynthetic genes are abundant in bacterial genomes, little is known about them. We could show that the pyreudione synthase is a multispecific enzyme that uses a Te domain to perform a Dieckmann-type cyclization. In the second part of this project, we describe a platform to identify novel natural products within the amoeba–bacteria interaction. We identified a novel nonribosomal peptide and novel butenolides. We named these lactones styrolides and we were able to elucidate their biosynthesis, which starts from a glyceraldehyde-3-phosphate and a 3-oxo acid.

Publications

• Bacterial Alkaloid Biosynthesis: Structural Diversity via a Minimalistic Nonribosomal Peptide Synthetase” Cell Chem. Biol. 2018, 25, 659
  M. Klapper, D. Braga, G. Lackner, R. Herbst, P. Stallforth
  (See online at https://doi.org/10.1016/j.chembiol.2018.02.013)
• The Role of Bacterial Natural Products in Predator Defense” Synlett, 2018, 29, 537
  M. Klapper, J. Arp, M. Günther, P. Stallforth
  (See online at https://doi.org/10.1055/s-0037-1609226)
• “Synergistic activity of co-secreted natural products from amoebae-associated bacteria” Proc. Natl. Acad. Sci. USA. 2018, 115, 3758
  J. Arp, S. Götze, R. Mukherji, D. J. Mattern, M. García-Altares, M. Klapper, D. A. Brock, A. A. Brakhage, J. E. Strassmann, D. C. Queller, B. Bardl, K. Willing, G. Peschel, P. Stallforth
  (See online at https://doi.org/10.1073/pnas.1721790115)
• “Bioactivity and Mode of Action of Bacterial Tetramic Acids” ACS Chem. Biol. 2019, 14, 1693
  M. Klapper, A. Paschold, S. Zhang, C. Weigel, H.-M. Dahse, S. Götze, S. Pace, S. König, Z. Rao, L. Reimer, O. Werz, P. Stallforth
  (See online at https://doi.org/10.1021/acschembio.9b00388)
• “Structure Elucidation of the Syringafactin Lipopeptides Provides Insight in the Evolution of Nonribosomal Peptide Synthetases” Chem. Sci. 2019, 10, 10979
  S. Götze, J. Arp, G. Lackner, S. Zhang, H. Kries, M. Klapper, M. García- Altares, K. Willing, M. Günther, P. Stallforth
  (See online at https://doi.org/10.1039/c9sc03633d)
• “Biosynthesis of Pseudomonas- Derived Butenolides” Angew. Chem. Int. Ed. 2020, 59, 5607
  M. Klapper, K. Schlabach, A. Paschold, S. Zhang, S. Chowdhury, K.-D. Menzel, M. A. Rosenbaum, P. Stallforth
  (See online at https://doi.org/10.1002/anie.201914154)