The Chemistry of microbial dark matter

Most bacteria are as-yet unculturable. This "microbial dark matter" includes numerous phylum-level lineages without cultivated members. Our group focuses on host-associated microbiomes, and showed that uncultivated bacteria are a rich resource of bioactive natural products.

Marine sponges are rich sources of bioactive natural products

Most of these sponges are not available in quantities that permit drug development and production. We showed that symbiotic bacteria are the true producers of many of sponge-derived compounds. Since these symbionts usually do not grow in culture, we develop efficient methods

to isolate biosynthetic gene clusters from sponge metagenomes (= multiple genomes),
to identify the producers,
and to express the genes in culturable bacteria that serve as renewable supplies.

These insights create new avenues for sustainable, biotechnological production of rare marine drug candidates - one of the lab's current priorities.

Enlarged view: Overview on the Piel lab's sponge research — A) The Piel lab's favorite sponge workhorses: Theonella swinhoei and Mycale hentscheli. B) Images of the Theonella bacterial symbionts Entotheonella (blue) and Poriflexus (colorless). C) Natural products from bacterial sponge symbionts. Polytheonamide is made by Entotheonella and aurantoside by Poriflexus bacteria (both from Theonella). Peloruside is produced by an unknown bacterium from the Mycale microbiome.

To date, our collaborative work has uncovered three distinct talented lineages: Entotheonella, Poriflexus, and Eudoremicrobiaceae. Entotheonella symbionts belong to a new, uncultivated candidate phylum that we have named 'Tectomicrobia'. Being present in many sponges, each Entotheonella variant produces distinct, large sets of bioactive compounds. We also showed that some chemically rich sponges, like Mycale hentscheli, associate with multiproducer microbiomes in which many members jointly synthesize a toxin cocktail.

Pederin structure and sources of pederin-analogs — Paederus beetles release pederin as chemical defense. Pederin-like compounds were isolated from other organisms like sponges, psyllids and lichen. Later, we and others found that symbiotic bacteria are the true producers of these compounds.

In addition to sponges, we contributed insights into metabolic functions of bacteria associated with various other hosts, including insects, lichens, and plants.

Related publications (selection)

Peters EE, Cahn JKB, Lotti A, Gavriilidou A, Steffens UAE, Loureiro C, Schorn MA, Cárdenas P, Vickneswaran N, Crews P, Sipkema D, Piel J. "Distribution and diversity of 'Tectomicrobia', a deep-branching uncultivated bacterial lineage harboring rich producers of bioactive metabolites." ISME Commun. (2023) 3, 1, 50. external pageAbstract

Kogawa M, Miyaoka R, Hemmerling F, Ando M, Yura K, Ide K, Nishikawa Y, Hosokawa M, Ise Y, Cahn JKB, Takada K, Matsunaga S, Mori T, Piel J, Takeyama H. "Single-cell metabolite detection and genomics reveals uncultivated talented producer." PNAS Nexus (2022) 1, 1, pgab007. external pageAbstract

Dieterich CL, Probst SI, Ueoka R, Sandu I, Schäfle D, Molin MD, Minas HA, Costa R, Oxenius A, Sander P, Piel J. "Aquimarins, Peptide Antibiotics with Amino-Modified C-Termini from a Sponge-Derived Aquimarina sp. Bacterium." Angew. Chem. Int. Ed. (2022) 61, 8, e202115802. external pageAbstract

Rust M, Helfrich EJN, Freeman MF, Nanudorn P, Field CM, Rückert C, Kündig T, Page MJ, Webb VL, Kalinowski J, Sunagawa S, Piel J. "A multiproducer microbiome generates chemical diversity in the marine sponge Mycale hentscheli." PNAS (2020) 117, 17, 9508-9518. external pageAbstract

Mori T, Cahn JKB, Wilson MC, Meoded RA, Wiebach V, Martinez AFC, Helfrich EJN, Albersmeier A, Wibberg D, Dätwyler S, Keren R, Lavy A, Rückert C, Ilan M, Kalinowski J, Matsunaga S, Takeyama H, Piel J. "Single-bacterial genomics validates rich and varied specialized metabolism of uncultivated Entotheonella sponge symbionts." PNAS (2018) 8, 1718-1723. external pageAbstract

Ueoka R, Uria AR, Reiter S, Mori T, Karbaum P, Peters EE, Helfrich EJ, Morinaka BI, Gugger M, Takeyama H, Matsunaga S, Piel J. "Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms." Nat. Chem. Biol. (2015) 9, 705-12. external pageAbstract

M.C. Wilson, T. Mori, C. Rückert, A.R. Uria, M.J. Helf, K. Takada, C. Gernert, U.A.E. Steffens, N. Heycke, S. Schmitt, C. Rinke, E.J.N. Helfrich, A.O. Brachmann, C. Gurgui, T. Wakimoto, M. Kracht, M. Crüsemann, U. Hentschel, I. Abe, S. Matsunaga, J. Kalinowski, H. Takeyama, and J. Piel "An environmental bacterial taxon with a large and distinct metabolic repertoire". Nature (2014) 506, 7486, 58-62. external pageAbstract

M.F. Freeman, C. Gurgui, M.J. Helf, B.I. Morinaka, A.R. Uria, N.J. Oldham, H.-G. Sahl, S. Matsunaga, J. Piel “Metagenome mining reveals polytheonamides as modified ribosomal peptides” Science (2012) 338, 387-390. external pageAbstract

K.M. Fisch, C. Gurgui, N. Heycke, S.A. van der Sar, S.A. Anderson, V.L. Webb, S. Taudien, M. Platzer, B.K. Rubio, S.J. Robinson, P. Crews, J. Piel "Polyketide assembly lines of uncultivated sponge symbionts from structure-based gene targeting" Nat. Chem. Biol. (2009) 7, 494-501. external pageAbstract

Zimmermann K, Engeser M, Blunt JW, Munro MH, Piel J. "Pederin-type pathways of uncultivated bacterial symbionts: analysis of O-methyltransferases and generation of a biosynthetic hybrid." JACS (2009) 131, 8, 2780-1. external pageAbstract

J. Piel, D. Hui, G. Wen, D. Butzke, M. Platzer, N. Fusetani, S. Matsunaga "Antitumor polyketide biosynthesis by a bacterial symbiont of the marine sponge Theonella swinhoei” PNAS (2004) 101, 16222-16227. external pageAbstract

Ueoka R, Sondermann P, Leopold-Messer S, Liu Y, Suo R, Bhushan A, Vadakumchery L, Greczmiel U, Yashiroda Y, Kimura H, Nishimura S, Hoshikawa Y, Yoshida M, Oxenius A, Matsunaga S, Williamson RT, Carreira EM, Piel J. "Genome-based discovery and total synthesis of janustatins, potent cytotoxins from a plant-associated bacterium." Nat Chem. (2022), 10, 1193-1201. external pageAbstract

Ueoka R, Meoded RA, Gran-Scheuch A, Bhushan A, Fraaije MW, Piel J. "Genome Mining of Oxidation Modules in trans-Acyltransferase Polyketide Synthases Reveals a Culturable Source for Lobatamides." Angew. Chem. Int. Ed. (2020) 59, 20, 7761-7765. external pageAbstract

Ueoka R, Bhushan A, Probst SI, Bray WM, Lokey RS, Linington RG, Piel J. "Genome-Based Identification of a Plant-Associated Marine Bacterium as a Rich Natural Product Source." Angew. Chem. Int. Ed. (2018) 57, 44, 14519-14523. external pageAbstract

Helfrich EJN, Vogel CM, Ueoka R, Schäfer M, Ryffel F, Müller DB, Probst S, Kreuzer M, Piel J, Vorholt JA. "Bipartite interactions, antibiotic production and biosynthetic potential of the Arabidopsis leaf microbiome." Nat. Microbiol. (2018) 8, 909-919. external pageAbstract

Kampa A, Gagunashvili AN, Gulder TAM, Daolio C, Godejohann M, Miao VPW , Piel J, Andrésson ÓS "Metagenomic natural product discovery in lichen provides evidence for specialized biosynthetic pathways in diverse symbioses" Proc. Natl. Acad. Sci. U. S. A. (2013), 110, E3129-3137 external pageAbstract

Brachmann AO, Probst SI, Rüthi J, Dudko D, Bode HB, Piel J. "A Desaturase-Like Enzyme Catalyzes Oxazole Formation in Pseudomonas Indolyloxazole Alkaloids." Angew. Chem. Int. Ed. (2021) 60, 16, 8781-8785. external pageAbstract

A. Nakabachi, R. Ueoka, K. Oshima, R. Teta, A. Mangoni, M. Gurgui, N.J. Oldham, G. van Echten-Deckert, K. Okamura, K. Yamamoto, H. Inoue, M. Ohkuma, Y. Hongoh, S.-Y. Miyagishima, M. Hattori, J. Piel, T. Fukatsu "Defensive bacteriome symbiont with a drastically reduced genome" Curr. Biol. (2013) 23, 1478-1484. external pageAbstract

J. Piel "A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles" Proc Natl Acad Sci U S A. (2002) Oct 29;99(22):14002-7. external pageAbstract