Natural Product Department

© Fraunhofer IME
© Fraunhofer IME

Research motivation

Nature has proven to be a valuable source of small bioactive molecules that can be applied in prevention and treatment of disease. Microbial derived natural products (NPs) play a particularly important role as active ingredients in pharmaceutical, veterinary and agricultural products. To continue this success story, it is necessary to identify new chemical entities showing desired biological properties.

 

Integrated Approach

The fully operational Natural Product Discovery Platform of Sanofi was transferred to the Fraunhofer Institute for Molecular Biology and Applied Ecology IME during a recent public-private partnership between the two parties [Fox 2014]. Thereby this well-established platform, covering the entire workflow from microbial strain to natural product, is now open to third parties. Moreover, we are constantly developing and adapting our techniques towards the specific needs of our clients. The core element of our department is one of the largest and well curated industrial strain collections worldwide. This unique collection consists of more than 110.000 talented NP producing microbes including actinomycetes, myxobacteria and a broad variety of fungi. Additionally, we are systematically expanding the phylogenetic diversity of the strain collection through isolation campaigns targeting rather underexplored microbes. This effort is facilitated by highly miniaturized cultivation approaches based on droplet-microfluidics technology.

Using these resources, we are generating microbial NP-extracts and purifying compounds of interest. These extracts and compounds are ready-to-screen for indications in human and veterinary medicine (e.g. antibiotics, anti-nematode) as well as agriculture (e.g. insecticides, fungicides, herbicides). Our NP discovery platform is complemented by state of the art analytics basing on a unique reference compound database covering more than 1500 pure natural products.


The Natural Product department has successfully performed several collaborative research projects with pharmaceutical, animal health and agrochemical companies over the last years. Our team has gained the expertise to efficiently perform goal-oriented projects towards the translation of innovation into marketable products.

 

Contract analytics and NP research platform:

Projects at the Fraunhofer IME often begin with analytical services for characterization of our clients’ samples and products. These include:

• Bioactivity screenings
• Identification of bioactive ingredients
• Chemical dereplication
• Product optimization
• Isolation of active ingredients

Benefit from our extensive collection of microbes, microbial-derived products, biological and chemical data as well as from the collaboration with our experts, who are eager to participate in your challenging project.

 

Access to our unique bioresources

The Sanofi collection of microorganism, associated microbial NP extracts and purified compounds is the legacy of over 7 decades of committed industrial endeavors towards collecting, cultivating and extracting microbial compounds. This unique collection of over 110 000 microorganisms (all collected before 2014, Nagoya confirmed) is well curated and consists of 80 000+ Actinomycetes, 2000+ Myxobacteria, 1000+ Firmicutes and 25 000+ fungi. In addition, we also explore the under-investigated bacterial space and provide access to very rare phylogenetic branches as e.g. Acidobacteria. Our in house developed strain management database links the strain batch to biochemical, genetic and analytical data enabling us to identify and retrieve compounds with desired properties in parallel guaranteeing the data integrity of our customers. Our custom in house strain management system links each processed strain to biochemical, genetic and analytical data enabling us to identify and retrieve compounds with desired properties, while guaranteeing data integrity of our customers.

 

Source our high throughput screening facility

From multi-drug resistant bacteria to phytopathogenic fungi or parasites like helminthes: The screening facility of the IME-BR provides a variety of assays to identify extracts and pure compounds with the desired property. In addition to bioactivity determination, screening for specific enzymatic activity or PCR-based screenings of DNA extracts complete the picture. Besides a large selection of established test systems, the workflow allows flexible integration of new screens, according to the customer’s interests.

Standardized and automatized liquid handling accounts for low-volume, high throughput testing of samples and guarantees robust data at industrial standard.

 

Benefit from our unique analytical service

IME-BR disposes of a state-of-the-art UHPLC-MS based analytics platform for extract analysis and compound identification. Dereplication is carried out by extensive analysis of the UV, MS and MS/MS data, using our internal compound database as well as external databases for compound searches. Measurements are performed on an Agilent 1290 Infinity® LC system coupled to a maXisII™ (Bruker Daltronics) ESI-QTOF-ultrahigh resolution mass spectrometer. Metabolomic fingerprinting tools enable the chemical similarity analysis of extracts within large datasets and automatic annotation of known natural products therein, by comparison with our in-house compound database. The database can systematically be expanded by integration of further compound classes fitting the scope of any particular project (e.g. known antifungals, herbicides and toxins). Microfractionation and chemical dereplication of active fractions is employed for identifying causative agents behind crude extract activities. By extensive analysis of the UV, MS and MS/MS data, using our internal compound database as well as external databases for compound searches. This is complemented by molecular networking tools, employed for the automatic identification of families of compounds within large datasets, on the basis of their mass fragmentation pattern similarity.

YEAR Titel / Autor Medium
2022

Antidiabetic Profiling of Veramycins, Polyketides Accessible by Biosynthesis, Chemical Synthesis, and Precursor-Directed Modification

Dardić D, Böhringer N, Plaza A, Zubeil F, Pohl J, Sommer S, Padva L, Becker J, Patras MA, Bill M, Kurz M, Toti L, Görgens SW, Schuler SMM, Billion A, Schwengers O, Wohlfart P, Goesmann A, Tennagels N, Vilcinskas A, Hammann PE, Schäberle TF, Bauer A.

Org Chem Front
9, 1604-1615

DOI: 10.1039/D1QO01652K

2022

Antimicrobial, Insecticidal and Cytotoxic Activity of Linear Venom Peptides from the Pseudoscorpion Chelifer cancroides

Krämer J, Lüddecke T, Marner M, Maiworm E, Eichberg J, Hardes K, Schäberle TF, Vilcinskas A, Predel R.

Toxins
14, 58.

DOi: 10.3390/toxins1401005

2022

Bioactive Natural Products from Bacteroidetes 

Brinkmann S, Spohn MS, Schäberle TF.

 

Nat Prod Rep,
(ahead of print)

DOI: 10.1039/d1np00072a

2022

Discovery of Marine Natural Products as Promising Antibiotics against Pseudomonas aeruginosa

Li H, Maimaitiming M, Zhou Y, Li H, Wang P, Liu Y, Schäberle TF, Liu Z, Wang C-Y.

Accepted Mar Drugs
4;20(3):192.

DOI: 10.3390/md20030192                                                        

2022

Genomic and Chemical Decryption of the Bacteroidetes Phylum for Its Potential to Biosynthesize Natural Products

Brinkmann S, Kurz M, Patras MA, Hartwig C, Marner M, Leis B, Billion A, Kleiner Y, Bauer A, Toti L, Pöverlein C, Hammann PE, Vilcinskas A, Glaeser J, Spohn MS, Schäberle TF.

Microbiol Spectr,
e0247921 (ahead of print)

 

DOI: 10.1128/spectrum.02479-21

2022

Genome Mining-Guided Discovery and Characterization of the PKS-NRPS-Hybrid Polyoxyperuin produced by a Marine-Derived Streptomycete 

Kresna ID, Wuisan ZG, Pohl JM, Mettal U, Linares-Otoya V, Gand M, Marner M, Linares-Otoya L, Böhringer N, Vilcinskas A, Schäberle TF.

J Nat Prod,
85, 4, 888–898

DOI: 10.1021/acs.jnatprod.1c01018

2022

Identification, Characterization, and Synthesis of Natural Parasitic Cysteine Protease Inhibitors: Pentacitidins Are More Potent Falcitidin Analogues

Brinkmann S, Semmler S, Kersten C, Patras MA, Kurz M, Fuchs N, Hammerschmidt SJ, Legac J, Hammann PE, Vilcinskas A, Rosenthal PJ, Schirmeister T, Bauer A, Schäberle TF.

ACS Chem Biol,
18;17(3):576-589

DOI: 10.1021/acschembio.1c00861

2022

Trichoderma-Derived Pentapeptides from the Infected Nest Mycobiome of the Subterranean Termite Coptotermes testaceus

Oberpaul M, Spohn M, Brinkmann S, Mihajlovic S, Marner M, Patras MA, Toti L, Kurz M, Hammann PE, Vilcinskas A, Glaeser J, Schäberle TF.

Chembiochem
e202100698  (ahead of print)

 

DOI: 10.1002/cbic.202100698

2021

Novel Glycerophospholipid, Lipo- and N-acyl Amino Acids from Bacteroidetes: Isolation, Structure Elucidation and Bioactivity.

Bill M-K, Brinkmann S, Oberpaul M, Patras MA, Leis B, Marner M, Maitre MP, Hammann PE, Vilcinskas A, Schuler SMM, Schäberle TF.

Molecules
26 (17).

DOI: 10.3390/molecules26175195

2021

Mutasynthetic production and antimicrobial characterisation of Darobactin analogs.

Böhringer N, Green R, Liu Y, Mettal U, Marner M, Modaresi SM, Jakob RP, Wuisan ZG, Maier T, Iinishi A, Hiller S, Lewis K, Schäberle TF. 

Microbiol Spectr
9, Issue 3, e01535-21. 

DOI: 10.1128/spectrum.01535-21

2021

Heterologous Expression of Pseudouridimycin and Description of the Corresponding Minimal Biosynthetic Gene Cluster.

Böhringer N, Patras MA, Schäberle TF.

Molecules
26 (2).

DOI: 10.3390/molecules26020510

2021

Two-step generation of monodisperse agarose-solidified double emulsions (w/w/o) excluding an inner oil barrier.

Brinkmann S, Oberpaul M, Glaeser J, Schäberle TF. 

MethodsX
8, 101565

DOI: 10.1016/j.mex.2021.101565

2021

Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C

Edelmann D, Leinberger FH, Schmid NE, Oberpaul M, Schäberle TF, Berghoff BA. 

Microorganisms
9(5), 943. 

DOI: 10.3390/microorganisms9050943

2021

Post-transcriptional deregulation of the tisB/istR-1 toxin–antitoxin system promotes SOS-independent persister formation in Escherichia coli

Edelmann D, Oberpaul M, Schäberle TF, Berghoff BA. 

Environmental microbiology reports
13(2), 159-168. 

DOI: 10.1111/1758-2229.12919

2021

Natural Merosesquiterpenes Activate the DNA Damage Response via DNA Strand Break Formation and Trigger Apoptotic Cell Death in p53-Wild-Type and Mutant Colorectal Cancer

Jiso A, Demuth P, Bachowsky M, Haas M, Seiwert N, Heylmann D, Rasenberger B, Christmann M, Dietrich L, Brunner T, Riyanti R, Schäberle TF, Plubrukarn A, Fahrer J. 

Cancers
13, 3282. 

DOI: 10.3390/cancers13133282

2021

Evaluation of the Floyocidin scaffold as an anti-tuberculosis hit series.

Kleiner Y, Pöverlein C, Klädtke J, Kurz M, König H, Becker J, Mihajlovic S, Zubeil F, Marner M, Vilcinskas A, Schäberle TF, Hammann PE, Schuler SMM, Bauer A. 

 ChemMedChem

DOI: 10.1002/cmdc.202100644

2021

In vitro characterization of 3-chloro-4-hydroxybenzoic acid building block formation in ambigol biosynthesis

Kresna IDM, Linares-Otoya L, Milzarek T, Duell ER, Mir Mohseni M, Mettal U, König GM, Gulder TAM, Schäberle TF. 

Organic & biomolecular chemistry
10, 2302-2311. 

DOI: 10.1039/D0OB02372H

2021

A series of meroterpenoids with rearranged skeletons from an endophytic fungus Penicillium sp. GDGJ-285

Mo T-X, Huang X-S, Zhang W-X, Schäberle TF, Qin J-K, Zhou D-X, Qin X-Y, Xu Z-L, Li J, Yang R-Y. 

Organic chemistry frontiers
8 (10), 2232-2241. 

DOI: 10.1039/D1QO00173F

2021

Combination of high-throughput microfluidics and FACS technologies to leverage the numbers game in natural product discovery.

Oberpaul M, Brinkmann S, Marner M, Mihajlovic S, Leis B, Patras MA, Hartwig C, Vilcinskas A, Hammann PE, Schäberle TF, Glaeser J, Spohn M.

Microbial Biotechnology
2021 Jun 24.

DOI: 10.1111/1751-7915.13872

2021

Optimization of heterologous Darobactin A expression and identification of the minimal biosynthetic gene cluster

Wuisan ZG, Kresna IDM, Böhringer N, Lewis K, Schäberle TF. 

Metabolic Engineering
66, 123-136. 

DOI: 10.1016/j.ymben.2021.04.007

2020

The Gram-Positive Bacterium Leuconostoc pseudomesenteroides Shows Insecticidal Activity against Drosophilid and Aphid Pests. 

Hiebert N, Kessel T, Skaljac M, Spohn M, Vilcinskas A, Lee KZ.

Insects
11 (8).

DOI: 10.3390/insects11080471

2020

Molecular Networking-Guided Discovery and Characterization of Stechlisins, a Group of Cyclic Lipopeptides from a Pseudomonas sp.

Marner M, Patras MA, Kurz M, Zubeil F, Förster F, Schuler S, Bauer A, Hammann P, Vilcinskas A, Schäberle TF, Glaeser J.

Journal of Natural Products
83 (9), 2607-2617.

DOI: 10.1021/acs.jnatprod.0c00263

2020

High-Throughput cultivation for the selective isolation of Acidobacteria from termite nests. 

Oberpaul M, Zumkeller CM, Culver T, Spohn M, Mihajlovic S, Leis B, Glaeser SP, Plarre R, McMahon DP, Hammann P, Schäberle TF, Glaeser J, Vilcinskas A.

Frontiers in Microbiology
11(597628).

DOI: 10.3389/fmicb.2020.597628

2020

Sustainable Low-Volume Analysis of Environmental Samples by Semi-Automated Prioritization of Extracts for Natural Product Research (SeaPEPR).

Riyanti R, Marner M, Hartwig C, Patras MA, Wodi SIM, Rieuwpassa FJ, Ijong FG, Balansa W, Schäberle TF.

Marine Drugs
18 (12)

DOI: 10.3390/md18120649

2019

A new antibiotic selectively kills Gram-negative pathogens.

Imai Y, Meyer KJ, Iinishi A, Favre-Godal Q, Green R, Manuse S, Caboni M, Mori M, Niles S, Ghiglieri M, Honrao C, Ma X, Guo JJ, Makriyannis A, Linares-Otoya L, Böhringer N, Wuisan ZG, Kaur H, Wu R, Mateus A, Typas A, Savitski MM, Espinoza JL, O’Rourke A, Nelson KE, Hiller S, Noinaj N, Schäberle TF, D’Onofrio A, Lewis K.

Nature
576 (7787), 459-464

DOI: 10.1038/s41586-019-1791-1

2019

Transmission of a Protease-Secreting Bacterial Symbiont Among Pea Aphids via Host Plants. 

Skaljac M, Vogel H, Wielsch N, Mihajlovic S, Vilcinskas A.

Frontiers in physiology
2019, 10, 438.

DOI: 10.3389/fphys.2019.00438

2018

Profiling antimicrobial peptides from the medical maggot Lucilia sericata as potential antibiotics for MDR Gram-negative bacteria.

Hirsch R, Wiesner J, Marker A, Pfeifer Y, Bauer A, Hammann PE, Vilcinskas A. 

Journal of Antimicrobial Chemotherapy
74 (1), 96-107.

DOI: 10.1093/jac/dky386

2017

Svetamycins A–G, Unusual Piperazic Acid-Containing Peptides from Streptomyces sp.

Dardić D, Lauro G, Bifulco G, Laboudie P, Sakhaii P, Bauer A, Vilcinskas A, Hammann PE, Plaza A.

The Journal of Organic Chemistry
82 (12), 6032-6043.

DOI: 10.1021/acs.joc.7b00228

2014

Fraunhofer to mine Sanofi microbial collection.

Fox, JL.

Nat Biotechnol
32, 305

DOI: 10.1038/nbt0414-305a