Until 2022

Since the development of microbes and higher eukaryotes coevolution has resulted in specific interaction mechanisms. It is well known that symbiotic bacteria and fungi influence the life cycle, and are essential for the homeostasis of many eukaryotes. However, in most cases, the factors driving and influencing the cross-kingdom interactions are unknown.

We focus on the structural identification of microbial chemical mediators that are important to maintain the symbiotic life style of the producing organisms.

To study the chemical signals we apply state-of-the-art analytical tools:

  • Analytical Chemistry (UHPLC, UHPLC-MS, NMR, MALDI etc.)
  • Genome Mining and Molecular Biology
  • Organic Synthesis (total synthesis and natural product derivatization)

Natural Products of Microbial Symbionts of Termites

Fungus-growing termites rear a symbiotic fungus as a food source in specialized combs. Termites have developed several strategies to combat invading fungi species, which can be life-threatening to the insect colony. Especially defensive symbionts support the homeostasis of the colony by secretion of selective antimicrobial and antifungal products.

Natural Products of Microbial Symbionts of Hydractinia

Natural products present in bacterial biofilm induce morphogenesis of larvae of the marine hydroid polyp Hydractinia echinata.

Head

Christine Beemelmanns
Head

Termites and their symbionts

Studying the microbiome of social insects, such as termites, helps to identify new aspects of small-molecule mediated symbiotic relations. At the same time it serves platform to identify new antibacterial and antifungal agents.

Fungus-growing termites

The fungus-growing termite system is a prime example of multilateral symbiosis. The ancient farming symbiosis involves a termite host (Macrotermitinae), a specialized fungal mutualist (Termitomyces) maintained in an optimized fungal garden system (fungus comb), the presence of complex and highly adapted bacterial communities within the insect gut and fungus comb, and the co-evolved garden weed (Pseudoxylaria).

Natural products from protective symbionts

Within this project, we aim to isolate, characterize and understand the role of natural products produced by microorganisms associated with fungus-growing termites. We used various different culturing techniques to isolate termite-associated microbes and pursued the whole genome sequence of several key isolates. Subsequent chemical analysis of our isolates in axenic and co-cultures revealed several new natural product classes showing a diverse set of biological activities.

Biosynthetic pathway analysis

We have sequenced the genomes of selected new microbial species to analyze their biosynthetic potential and potentially detect new natural products. The comparative analysis of the acquired genomic information likely reveals new biosynthetic enzymes and new biochemical transformations.

Documentation

Termine Fungiculture – A Hidden Treasure Trove

Wie ein Antibiotikacocktail Insekten schützt

Funding

  • ChemBioSys (DFG) seit 2016
  • BiBiMac (DFG-ANR) ab 2018

Our collaborations

Microbial Symbionts of Hydractinia

Microbes associated with marine invertebrates are well-known to harbor an enormous biosynthetic potential. We combine new bioassays, genome sequencing and mining strategies to identify the encoded secondary metabolites with unique chemical scaffolds and potential pharmaceutical application.

Microorganisms protect and shape the colonial hydroid polyp Hydraktinia

Morphogenic Signaling Molecules

More and more examples show that bacterially produced small molecules contribute to the host’s fitness and development by acting as biological information carrier to maintain and modulate the multilateral interaction network. But fully characterized examples are still rare, and the mode-of-actions of those molecules are often not well understood.

We are investigating the model system Hydractinia echinata, a marine hydroid polyp, to identify key metabolites that induce biofouling.

The life cycle of the marine hydroid polyp H. echinata has a motile (larvae) and sessil reproductive phase (polyp). The irreversible morphogenesis from the motile larvae to the sessile primary polyp is induced by specific molecules from Pseudoalteromonas spp. But the structure determination and and mode of action of the signaling molecules has been so far elusive. We use a broad range of molecular biology methods to identify the bacterial cues and the receptor in the marine hydroid polyp to understand the interaction mechanisms in more detail.

 

Natural product synthesis and derivatisation

Many natural products are only produced in minor amounts and a full structural characterization is nearly impossible. In addition, many pharmaceutically interesting compounds are too toxic and need derivatisation to improve their pharmacological properties.

Therefore, we are establishing synthetic strategies towards sphingoid-type natural products and functionalized lipids, which represent important signaling molecules in our ecological mdoel systems. 

Synthesis of new NRPS-derived natural products

Based on a comparative genome analysis, we were able to isolate a new natural product - barnesin A. Further bioactivity studies showed that barnesin A is a cysteine ​​protease inhibitor with nanomolar activity. The total synthesis enabled further structural activity studies.

For more details, see Maja's article in ACS ChemBio!

Publications

Bissell AU, Rautschek J, Hoefgen S, Raguž L, Mattern DJ, Saeed N, Janevska S, Jojić K, Huang Y, Kufs JE, Herboeck B, Guo H, Hillmann F, Beemelmanns C, Valiante V (2022) Biosynthesis of the sphingolipid inhibitors sphingofungins in filamentous fungi requires aminomalonate as a metabolic precursor. ACS Chem Biol 17(2), 386-394.
Grosse M, Günther K, Jordan PM, Roman D, Werz O, Beemelmanns C (2022) Synthesis of functionalized δ-hydroxy-β-keto esters and evaluation of their anti-inflammatory properties. ChemBioChem 23(9), e202200073.
Guo H, Daniel JM, Seibel E, Burkhardt I, Conlon BH, Görls H, Vassão DG, Dickschat JS, Poulsen M, Beemelmanns C (2022) Insights into the metabolomic capacity of podaxis and isolation of podaxisterols A-D, ergosterol derivatives carrying nitrosyl cyanide-derived modifications. J Nat Prod 85(9), 2159-2167. (Review)
Guo H, Rischer M, Beemelmanns C (2022) Signalling molecules inducing metamorphosis in marine organisms. Nat Prod Rep 39(9), 1833-1855. (Review)
Hoefgen S, Bissell AU, Huang Y, Gherlone F, Raguž L, Beemelmanns C, Valiante V (2022) Desaturation of the sphingofungin polyketide tail results in increased serine palmitoyltransferase inhibition. Microbiol Spectr 10(5), e0133122.
Kreuzenbeck NB, Seibel E, Schwitalla JW, Fricke J, Conlon BH, Schmidt S, Hammerbacher A, Köllner TG, Poulsen M, Hoffmeister D, Beemelmanns C (2022) Comparative genomic and metabolomic analysis of Termitomyces species provides insights into the terpenome of the fungal cultivar and the characteristic odor of the fungus garden of Macrotermes natalensis termites. mSystems 7(1), e0121421.
Lee SR, Schalk F, Schwitalla JW, Guo H, Yu JS, Song M, Jung WH, de Beer ZW, Beemelmanns C, Kim KH (2022) GNPS**-guided discovery of madurastatins A1, A2, E1, F, and G1, siderophores from the termite-associated Actinomadura sp. RB99. Chemistry 28(36), e202200612.
Moghaddam Amri J, Guo H, Willing K, Wichard T, Beemelmanns C (2022) Identification of the new prenyltransferase Ubi-297 from marine bacteria and elucidation of its substrate specificity. Beilstein J Org Chem 10, 722-731.
Raguž L, Peng CC, Rutaganira FUN, Krüger T, Stanisic A, Jautzus T, Kries H, Kniemeyer O, Brakhage AA, King N, Beemelmanns C (2022) Total synthesis and functional evaluation of IORs, sulfonolipid-based inhibitors of cell differentiation in Salpingoeca rosetta. Angew Chem Int Ed 61(41), e202209105.
Sauer M, Beemelmanns C (2022) Application of pyrrolo-protected amino aldehydes in the stereoselective synthesis of anti 1,2-amino alcohols. ChemCom 58(64), 8990-8993.