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

Total Synthesis of Floyocidin B: 4,5-Regioselective Functionalization of 2-Chloropyridines

Kleiner Y, Bauer A, Hammann P, Schuler SMM, Pöverlein C.

Chemistry 5(1), 168-178

DOI: 10.3390/chemistry5010014


Antimicrobial Activity of Ceftazidime-Avibactam, Ceftolozane-Tazobactam, Cefiderocol, and Novel Darobactin Analogs against Multidrug-Resistant Pseudomonas aeruginosa Isolates from Pediatric and Adolescent Cystic Fibrosis Patients

Marner M, Kolberg L, Horst L, Böhringer N, Hübner J, Kresna DM, Liu Y, Mettal U, Wang L, Meyer-Bühn M, Mihajlovic S, Kappler M, Schäberle  TF, von Both U.

Microbiol Spectr.

DOI: 10.1128/spectrum.04437-22


Bioactive Natural Products from Bacteroidetes 

Brinkmann S, Spohn MS, Schäberle TF.

Nat. Prod. Rep. 39, 1045-1065

DOI: 10.1039/d1np00072a


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.

Mar Drugs 4;20(3):192

DOI: 10.3390/md20030192                                                        


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.

Antimicrobial Chemotherapy 10 (3)

DOI: 10.1128/spectrum.02479-21


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


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


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, 23 (10), e202100698  

DOI: 10.1002/cbic.202100698


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


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


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


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


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


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


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


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. 


DOI: 10.1002/cmdc.202100644


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


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


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


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


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


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


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


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


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


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


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


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


Fraunhofer to mine Sanofi microbial collection.

Fox, JL.

Nat Biotechnol 32, 305

DOI: 10.1038/nbt0414-305a