Publications

2025

[112] Zdouc, M. M., Blin, K., Louwen, N. L., et al. MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration, Nucleic Acids Research, Volume 53, Issue D1, 6 January 2025, Pages D678–D690, https://doi.org/10.1093/nar/gkae1115

Abstract

Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015. Since its conception, MIBiG has been regularly updated to expand data coverage and remain up to date with innovations in natural product research. Here, we describe MIBiG version 4.0, an extensive update to the data repository and the underlying data standard. In a massive community annotation effort, 267 contributors performed 8304 edits, creating 557 new entries and modifying 590 existing entries, resulting in a new total of 3059 curated entries in MIBiG. Particular attention was paid to ensuring high data quality, with automated data validation using a newly developed custom submission portal prototype, paired with a novel peer-reviewing model. MIBiG 4.0 also takes steps towards a rolling release model and a broader involvement of the scientific community. MIBiG 4.0 is accessible online at https://mibig.secondarymetabolites.org/.

2024

[111] Sauer, M., Kany, A. M., Götze, S., Müller, R., Beemelmanns, C. Structure Revision of Halisphingosine A via Total Synthesis and Bioactivity Studies. Angew. Chem. Int. Ed. 2024, 63, e202416036. https://doi.org/10.1002/anie.202416036

Abstract

Sphingoid bases are important bioactive lipids found in a variety of organisms, serving as the backbone of sphingolipids, which regulate essential physiological processes. Here we describe the total synthesis and structure revision of halisphingosine A, a sphingoid base initially isolated from marine sponges. To address inconsistencies in the NMR interpretation of this natural product, we developed a synthetic route involving a late-stage enantioselective Henry reaction that allows access to multiple stereoisomers of the proposed halisphingosine A core structure. Our library of 32 fully characterized synthetic stereoisomers enabled us to rectify the structure of halisphingosine A as (2R,3R,8R,Z)-2-aminooctadec-9-ene-1,3,8-triol, and to pursue further structure?activity relation (SAR) studies regarding their antimicrobial and cytotoxic potential. In summary, our study offers a yet unreported compound library along with validated analytical datasets of marine sphingoid base derivatives, which significantly affects future ecometabolomic marine research and will facilitate the identification of inhibitors of sphingolipid metabolism or antagonists of sphingolipid base-sensing receptors.

[110] Schmidt, S., Murphy, R., Vizueta, J. et al. Comparative genomics unravels a rich set of biosynthetic gene clusters with distinct evolutionary trajectories across fungal species (Termitomyces) farmed by termites. Commun Biol 7, 1269 (2024). https://doi.org/10.1038/s42003-024-06887-y

Abstract

The use of compounds produced by hosts or symbionts for defence against antagonists has been identified in many organisms, including in fungus-farming termites (Macrotermitinae). The obligate mutualistic fungus Termitomyces plays a pivotal role in plant biomass decomposition and as the primary food source for these termites. Despite the isolation of various specialized metabolites from different Termitomyces species, our grasp of their natural product repertoire remains incomplete. To address this knowledge gap, we conducted a comprehensive analysis of 39 Termitomyces genomes, representing 21 species associated with members of five termite host genera. We identified 754 biosynthetic gene clusters (BGCs) coding for specialized metabolites and categorized 660 BGCs into 61 biosynthetic gene cluster families (GCFs) spanning five compound classes. Seven GCFs were shared by all 21 Termitomyces species and 21 GCFs were present in all genomes of subsets of species. Evolutionary constraint analyses on the 25 most abundant GCFs revealed distinctive evolutionary histories, signifying that millions of years of termite-fungus symbiosis have influenced diverse biosynthetic pathways. This study unveils a wealth of non-random and largely undiscovered chemical potential within Termitomyces and contributes to our understanding of the intricate evolutionary trajectories of biosynthetic gene clusters in the context of long-standing symbiosis.

[109] Seibel, E., Um, S., Bodawatta, K.H. et al. Bacteria from the Amycolatopsis genus associated with a toxic bird secrete protective secondary metabolites. Nat Commun 15, 8524 (2024). https://doi.org/10.1038/s41467-024-52316-3

Abstract

Uropygial gland secretions of birds consist of host and bacteria derived compounds and play a major sanitary and feather-protective role. Here we report on our microbiome studies of the New Guinean toxic bird Pachycephala schlegelii and the isolation of a member of the Amycolatopsis genus from the uropygial gland secretions. Bioactivity studies in combination with co-cultures, MALDI imaging and HR-MS/MS-based network analyses unveil the basis of its activity against keratinolytic bacteria and fungal skin pathogens. We trace the protective antimicrobial activity of Amycolatopsis sp. PS_44_ISF1 to the production of rifamycin congeners, ciromicin A and of two yet unreported compound families. We perform NMR and HR-MS/MS studies to determine the relative structures of six members belonging to a yet unreported lipopeptide family of pachycephalamides and of one representative of the demiguisins, a new hexapeptide family. We then use a combination of phylogenomic, transcriptomic and knock-out studies to identify the underlying biosynthetic gene clusters responsible for the production of pachycephalamides and demiguisins. Our metabolomics data allow us to map molecular ion features of the identified metabolites in extracts of P. schlegelii feathers, verifying their presence in the ecological setting where they exert their presumed active role for hosts. Our study shows that members of the Actinomycetota may play a role in avian feather protection.

[108] Schmartz, G.P., Rehner, J., Gund, M.P. et al. Decoding the diagnostic and therapeutic potential of microbiota using pan-body pan-disease microbiomics. Nat Commun 15, 8261 (2024). https://doi.org/10.1038/s41467-024-52598-7

Abstract

The human microbiome emerges as a promising reservoir for diagnostic markers and therapeutics. Since host-associated microbiomes at various body sites differ and diseases do not occur in isolation, a comprehensive analysis strategy highlighting the full potential of microbiomes should include diverse specimen types and various diseases. To ensure robust data quality and comparability across specimen types and diseases, we employ standardized protocols to generate sequencing data from 1931 prospectively collected specimens, including from saliva, plaque, skin, throat, eye, and stool, with an average sequencing depth of 5.3 gigabases. Collected from 515 patients, these samples yield an average of 3.7 metagenomes per patient. Our results suggest significant microbial variations across diseases and specimen types, including unexpected anatomical sites. We identify 583 unexplored species-level genome bins (SGBs) of which 189 are significantly disease-associated. Of note, the existence of microbial resistance genes in one specimen was indicative of the same resistance genes in other specimens of the same patient. Annotated and previously undescribed SGBs collectively harbor 28,315 potential biosynthetic gene clusters (BGCs), with 1050 significant correlations to diseases. Our combinatorial approach identifies distinct SGBs and BGCs, emphasizing the value of pan-body pan-disease microbiomics as a source for diagnostic and therapeutic strategies.

[107] Pakkir Shah, A.K., Walter, A., Ottosson, F. et al. Statistical analysis of feature-based molecular networking results from non-targeted metabolomics data. Nat Protoc (2024). https://doi.org/10.1038/s41596-024-01046-3

Abstract

Feature-based molecular networking (FBMN) is a popular analysis approach for liquid chromatography–tandem mass spectrometry-based non-targeted metabolomics data. While processing liquid chromatography–tandem mass spectrometry data through FBMN is fairly streamlined, downstream data handling and statistical interrogation are often a key bottleneck. Especially users new to statistical analysis struggle to effectively handle and analyze complex data matrices. Here we provide a comprehensive guide for the statistical analysis of FBMN results, focusing on the downstream analysis of the FBMN output table. We explain the data structure and principles of data cleanup and normalization, as well as uni- and multivariate statistical analysis of FBMN results. We provide explanations and code in two scripting languages (R and Python) as well as the QIIME2 framework for all protocol steps, from data clean-up to statistical analysis. All code is shared in the form of Jupyter Notebooks (https://github.com/Functional-Metabolomics-Lab/FBMN-STATS). Additionally, the protocol is accompanied by a web application with a graphical user interface (https://fbmn-statsguide.gnps2.org/) to lower the barrier of entry for new users and for educational purposes. Finally, we also show users how to integrate their statistical results into the molecular network using the Cytoscape visualization tool. Throughout the protocol, we use a previously published environmental metabolomics dataset for demonstration purposes. Together, the protocol, code and web application provide a complete guide and toolbox for FBMN data integration, cleanup and advanced statistical analysis, enabling new users to uncover molecular insights from their non-targeted metabolomics data. Our protocol is tailored for the seamless analysis of FBMN results from Global Natural Products Social Molecular Networking and can be easily adapted to other mass spectrometry feature detection, annotation and networking tools.

[106] Lee, S.R., Dayras, M., Fricke, J., Guo, H., Balluff, S., Schalk, F., Yu, J.S., Jeong, S.Y., Morgenstern, B., Slippers, B., Beemelmanns, C., Kim, K.H. Molecular networking and computational NMR analyses uncover six polyketide-terpene hybrids from termite-associated Xylaria isolates. Commun Chem 7, 129 (2024). https://doi.org/10.1038/s42004-024-01210-6

Abstract

Fungi constitute the Earth’s second most diverse kingdom, however only a small percentage of these have been thoroughly examined and categorized for their secondary metabolites, which still limits our understanding of the ecological chemical and pharmacological potential of fungi. In this study, we explored members of the co-evolved termite-associated fungal genus Xylaria and identified a family of highly oxygenated polyketide-terpene hybrid natural products using an MS/MS molecular networking-based dereplication approach. Overall, we isolated six no yet reported xylasporin derivatives, of which xylasporin A (1) features a rare cyclic-carbonate moiety. Extensive comparative spectrometric (HRMS²) and spectroscopic (1D and 2D NMR) studies allowed to determine the relative configuration across the xylasporin family, which was supported by chemical shift calculations of more than 50 stereoisomers and DP4+ probability analyses. The absolute configuration of xylasporin A (1) was also proposed based on TDDFT-ECD calculations. Additionally, we were able to revise the relative and absolute configurations of co-secreted xylacremolide B produced by single x-ray crystallography. Comparative genomic and transcriptomic analysis allowed us to deduce the putative biosynthetic assembly line of xylasporins in the producer strain X802, and could guide future engineering efforts of the biosynthetic pathway.

[105] Seibold PS, Dörner S, Fricke J, Schäfer T, Beemelmanns C, Hoffmeister D. Genetic regulation of L-tryptophan metabolism in Psilocybe mexicana supports psilocybin biosynthesis. Fungal Biol Biotechnol. 2024 Apr 25;11(1):4. doi: 10.1186/s40694-024-00173-6 . PMID: 38664850 ; PMCID: PMC11046786.

Abstract

Although Basidiomycota produce pharmaceutically and ecologically relevant natural products, knowledge of how they coordinate their primary and secondary metabolism is virtually non-existent. Upon transition from vegetative mycelium to carpophore formation, mushrooms of the genus Psilocybe use L-tryptophan to supply the biosynthesis of the psychedelic tryptamine alkaloid psilocybin with the scaffold, leading to a strongly increased demand for this particular amino acid as this alkaloid may account for up to 2% of the dry mass. Using Psilocybe mexicana as our model and relying on genetic, transcriptomic, and biochemical methods, this study investigated if L-tryptophan biosynthesis and degradation in P. mexicana correlate with natural product formation. Although Basidiomycota produce pharmaceutically and ecologically relevant natural products, knowledge of how they coordinate their primary and secondary metabolism is virtually non-existent. Upon transition from vegetative mycelium to carpophore formation, mushrooms of the genus Psilocybe use L-tryptophan to supply the biosynthesis of the psychedelic tryptamine alkaloid psilocybin with the scaffold, leading to a strongly increased demand for this particular amino acid as this alkaloid may account for up to 2% of the dry mass. Using Psilocybe mexicana as our model and relying on genetic, transcriptomic, and biochemical methods, this study investigated if L-tryptophan biosynthesis and degradation in P. mexicana correlate with natural product formation.

Abstract

The cosmopolitan marine Roseobacter clade is of global biogeochemical importance. Members of this clade produce sulfur-containing amino lipids (SALs) of importance for biofilm formation and marine surface colonization processes. Despite their physiological importance and abundance, SALs have only been explored through genomic mining approaches and lipidomic studies based on mass spectrometry, which left the relative and absolute structures of SALs unresolved hindering progress in biochemical and functional investigations. Here, we report the structural revision of a new group of SALs, which we named cysteinolides, using a combination of analytical techniques, isolation and degradation experiments and total synthetic efforts. Contrary to the previously proposed homotaurine-based structures, cysteinolides are composed of an N,O-acylated cysteinolic acid-containing head group carrying various different (α?hydroxy) carboxylic acids. We performed the first validated targeted-network based analysis, which allowed us to map the distribution and structural diversity of cysteinolides across bacterial lineages. Beyond offering structural insights, our research provides SAL standards and validated analytical data. This information holds significance for forthcoming investigations into bacterial sulfonolipid metabolism and biogeochemical nutrient cycling within marine environments.

[103] Milke, L., Kabuu, M., Zschoche, R. et al. A type III polyketide synthase cluster in the phylum Planctomycetota is involved in alkylresorcinol biosynthesis. Appl Microbiol Biotechnol 108, 239 (2024). https://doi.org/10.1007/s00253-024-13065-x.

Abstract

Members of the bacterial phylum Planctomycetota have recently emerged as promising and for the most part untapped sources of novel bioactive compounds. The characterization of more than 100 novel species in the last decade stimulated recent bioprospection studies that start to unveil the chemical repertoire of the phylum. In this study, we performed systematic bioinformatic analyses based on the genomes of all 131 described members of the current phylum focusing on the identification of type III polyketide synthase (PKS) genes. Type III PKSs are versatile enzymes involved in the biosynthesis of a wide array of structurally diverse natural products with potent biological activities. We identified 96 putative type III PKS genes of which 58 are encoded in an operon with genes encoding a putative oxidoreductase and a methyltransferase. Sequence similarities on protein level and the genetic organization of the operon point towards a functional link to the structurally related hierridins recently discovered in picocyanobacteria. The heterologous expression of planctomycetal type III PKS genes from strains belonging to different families in an engineered Corynebacterium glutamicum strain led to the biosynthesis of pentadecyl- and heptadecylresorcinols. Phenotypic assays performed with the heterologous producer strains and a constructed type III PKS gene deletion mutant suggest that the natural function of the identified compounds differs from that confirmed in other bacterial alkylresorcinol producers.

[102] Beemelmanns, C., Keller, A. & Müller, R. Mining the microbiota for antibiotics. Nat Microbiol 9, 13–14 (2024). https://doi.org/10.1038/s41564-023-01568-8.

Abstract

The antimicrobial agent epifadin, which is produced by the nasal commensal Staphylococcus epidermidis, has— despite its short half-life — broad-spectrum activity, including against Staphylococcus aureus.

2023

[101] Li G.S., Leal-Dutra C.A., Cuesta-Maté A., Beemelmanns C. et al. 2023. Resolution of eleven reported and five novel Podaxis species based on ITS phylogeny, phylo-
genomics, morphology, ecology, and geographic distribution. Persoonia 51: 257–279. https://doi.org/10.3767/persoonia.2023.51.07.

Abstract

The genus Podaxis was first described from India by Linnaeus in 1771, but several revisions of the genus have left the taxonomy unclear. Forty-four Podaxis species names and nine intraspecific varieties are currently accepted, but most fungarium specimens are labelled Podaxis pistillaris. Recent molecular analyses based on barcoding genes suggest that the genus comprises several species, but their status is largely unresolved. Here we obtained basidiospores and photographs from 166 fungarium specimens from around the world and generated a phylogeny based on rDNA internal transcribed spacer ITS1, 5.8S and ITS2 (ITS), and a phylogenomic analysis of 3 839 BUSCO genes from low-coverage genomes for a subset of the specimens. Combining phylogenetics, phylogenomics, morphology, ecology, and geographical distribution, spanning 250 years of collections, we propose that the genus includes at least 16 unambiguous species. Based on 10 type specimens (holotype, paratype, and syntype), four recorded species were confirmed, P. carcinomalis, P. deflersii, P. emerici, and P. farlowii. Comparing phylogenetic analysis with described species, including morphology, ecology, and distribution, we resurrected P. termitophilus and designated neotypes, epitypes, or lectotypes for five previously described species, P. aegyptiacus, P. africana, P. beringamensis, P. calyptratus, and P. perraldieri. Lastly, based on phylogenies and morphology of type material, we synonymized three reported species, P. algericus, P. arabicus, and P. rugospora with P. pistillaris, and described five new species that we named P. desolatus, P. inyoensis, P. mareebaensis, P. namaquensis, and P. namibensis.

[100] Schwitalla, J. W., Le, N.-T. H., et al. Heterologous expression of the cryptic mdk gene cluster and structural revision of maduralactomycin A. RSC Advances, 2023, 13, 34136 - 34144. https://doi.org/10.1039/D3RA05931F

Abstract

After conducting an in silico analysis of the cryptic mdk cluster region and performing transcriptomic studies, an integrative Streptomyces BAC Vector containing the mdk gene sequence was constructed. The heterologous expression of the mdk cluster in Streptomyces albus J1074 resulted in the production of the angucyclic product, seongomycin, which allowed for the assesment of its antibacterial, antiproliferative, and antiviral activities. Heterologous production was further confirmed by targeted knock-out experiments involving key regulators of the biosynthetic pathways. We were further able to revise the core structure of maduralactomycin A, using a computational approach.

[99] Seibel, E., Um, S., Dayras, M. et al. Genome mining for macrolactam-encoding gene clusters allowed for the network-guided isolation of β-amino acid-containing cyclic derivatives and heterologous production of ciromicin A. Commun Chem 6, 257 (2023). https://doi.org/10.1038/s42004-023-01034-w

Abstract

β-Amino acid-containing macrolactams represent a structurally diverse group of bioactive natural products derived from polyketides; however we are currently lacking a comprehensive overview about their abundance across bacterial families and the underlying biosynthetic diversity. In this study, we employed a targeted β-amino acid-specific homology-based multi-query search to identify potential bacterial macrolactam producers. Here we demonstrate that approximately 10% of each of the identified actinobacterial genera harbor a biosynthetic gene cluster (BGC) encoding macrolactam production. Based on our comparative study, we propose that mutations occurring in specific regions of polyketide synthases (PKS) are the primary drivers behind the variation in macrolactam ring sizes. We successfully validated two producers of ciromicin A from the genus Amycolatopsis, revised the composition of the biosynthetic gene cluster region mte of macrotermycins, and confirmed the ciromicin biosynthetic pathway through heterologous expression. Additionally, network-based metabolomic analysis uncovered three previously unreported macrotermycin congeners from Amycolatopsis sp. M39. The combination of targeted mining and network-based analysis serves as a powerful tool for identifying macrolactam producers and our studies will catalyze the future discovery of yet unreported macrolactams.

[98] Kreuzenbeck, N.B., Dhiman, S., Roman, D. et al. Isolation, (bio)synthetic studies and evaluation of antimicrobial properties of drimenol-type sesquiterpenes of Termitomyces fungi. Commun Chem 6, 79 (2023). https://doi.org/10.1038/s42004-023-00871-z

Abstract

Macrotermitinae termites have farmed fungi in the genus Termitomyces as a food source for millions of years. However, the biochemical mechanisms orchestrating this mutualistic relationship are largely unknown. To deduce fungal signals and ecological patterns that relate to the stability of this symbiosis, we explored the volatile organic compound (VOC) repertoire of Termitomyces from Macrotermes natalensis colonies. Results show that mushrooms emit a VOC pattern that differs from mycelium grown in fungal gardens and laboratory cultures. The abundance of sesquiterpenoids from mushrooms allowed targeted isolation of five drimane sesquiterpenes from plate cultivations. The total synthesis of one of these, drimenol, and related drimanes assisted in structural and comparative analysis of volatile organic compounds (VOCs) and antimicrobial activity testing. Enzyme candidates putatively involved in terpene biosynthesis were heterologously expressed and while these were not involved in the biosynthesis of the complete drimane skeleton, they catalyzed the formation of two structurally related monocyclic sesquiterpenes named nectrianolins.

[97] Albert T. H. Bartholomäus, Dávid Roman, Walid K. Al-Jammal, Prof. Dr. Ivan Vilotijević, Prof. Dr. Christine Beemelmann Synthesis of Aryl- and Alkyl-Containing 3-Methylene-5-hydroxy Esters via a Barbier Allylation Reaction EurJOC doi: 10.1002/ejoc.202300177

Abstract

The formation of C−C bonds via the allylation of carbonyl compounds has been widely applied in total syntheses. Amongst the many possible strategies, the Barbier-type allylation in aqueous media has received only moderate attention over the last decades despite its mild reaction conditions. In this study, we investigated the indium (In⁰) and zinc (Zn⁰) mediated Barbier allylation reaction to efficiently synthesize base-labile 3-methylene-5-hydroxy containing building blocks for natural product total synthesis. As model study we selected the allylation of lipidic undecanal with ethyl 3-(bromomethyl)but-3-enoate in the presence of either Zn⁰ or In⁰ and investigated the effects of additives on yields and selectivities. We then applied the optimized reaction conditions to sterically demanding allyl bromides and functionalized aromatic aldehydes yielding eleven new homoallylic alcohols, one of which was further transformed via oxidation and reduction sequences.

[96] Bodawatta KH, Hu H, Schalk F, Daniel JM, Maiah G, Koane B, Iova B, Beemelmanns C, Poulsen M, Jønsson KA. Multiple mutations in the Nav1.4 sodium channel of New Guinean toxic birds provide autoresistance to deadly batrachotoxin. Mol Ecol. 2023. doi: 10.1111/mec.16878.

Abstract

We examine genomic adaptations that could facilitate autoresistance to the diet-acquired potent neurotoxic alkaloid batrachotoxin (BTX) in New Guinean toxic birds. Our work documents two new toxic bird species and shows that toxic birds carry multiple mutations in the SCN4A gene that are under positive selection. This gene encodes the most common vertebrate muscle Nav channel (Nav1.4). Molecular docking results indicate that some of the mutations that are present in the pore-forming segment of the Nav channel, where BTX binds, could reduce its binding affinity.

[95] Fricke J, Schalk F, Kreuzenbeck NB, Seibel E, Hoffmann J, Dittmann G, Conlon BH, Guo H, Wilhelm de Beer Z, Vassão DG, Gleixner G, Poulsen M, Beemelmanns C. Adaptations of Pseudoxylaria towards a comb-associated lifestyle in fungus-farming termite colonies. ISME J. 2023, doi: 10.1038/s41396-023-01374-4.

Abstract

Capitalizing on viable Pseudoxylaria cultures from different termite colonies, we obtained genomes of seven and transcriptomes of two Pseudoxylaria isolates. Using a whole-genome-based comparison with free-living members of the genus Xylaria, we document that the association has been accompanied by significant reductions in genome size, protein-coding gene content, and reduced functional capacities related to oxidative lignin degradation, oxidative stress responses and secondary metabolite production. Functional studies based on growth assays and fungus-fungus co-cultivations, coupled with isotope fractionation analysis, showed that Pseudoxylaria only moderately antagonizes growth of the termite food fungus Termitomyces, and instead extracts nutrients from the food fungus biomass for its own growth

2022

[94] 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.

[93] Raguž L,^# Peng CC,^# Rutaganira FUN, Krüger T, Stanisic A, Jautzus T, Kries H, Kniemeyer O, Brakhage A, 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, e202209105.

Abstract

A new and modular synthesis of the rosette-inhibitor sulfonolipid IOR-1A and chemical probes was achieved via decarboxylative cross-coupling reaction of a desymmetrized tartaric acid derivatives and alkyl zinc reagents of choice. Synthesized congeners and bifunctional probes allowed to determine structure-activity relation to profile binding partners in producer and recipient for the first time.

[92] 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, e0133122.

Abstract

Sphingofungins belong to a group of structurally related sphingolipid inhibitors produced by fungi, which specifically inhibit serine palmitoyl transferases, enzymes catalyzing the initial step during sphingolipid biosynthesis. We identified and elucidated the biosynthetic gene cluster responsible for the biosynthesis of sphingofungins B, C, and D in Aspergillus fumigatus. In vitro analyses have shown that sphingofungin biosynthesis starts with the condensation of a C18 polyketide with the uncommon substrate aminomalonate.

[91] Guo H,* Rischer M, Beemelmanns C* (2022). Signalling molecules inducing metamorphosis in marine organisms. Nat Prod Rep 39(9), 1833-1855 (Review).

Abstract

Covering: findings from early 1980s until early 2022Microbial-derived cues of marine biofilms induce settlement and metamorphosis of marine organisms, a process responsible for the emergence of diverse flora and fauna in marine habitats. Although this phenomenon is known for more than 80 years, the research field has only recently gained much momentum. Here, we summarize the currently existing biochemical and microbial knowledge about microbial signalling molecules, con-specific signals, and synthetic compounds that induce or prevent recruitment, settlement, and metamorphosis in invertebrate larvae. We discuss the possible modes of action and conclude with perspectives for future research directions in the field of marine chemical ecology.

[90] 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.

Abstract

Serine palmitoyltransferase catalyzes the first step of the sphingolipid biosynthesis. Recently, sphingolipid homeostasis has been connected to several human diseases, making serine palmitoyltransferases an interesting therapeutic target. Known and efficient serine palmitoyltransferase-inhibitors are sphingofungins, a group of natural products isolated from fungi. To further characterize newly isolated sphingofungins, we designed an easy to use colorimetric serine palmitoyltransferase activity assay using FadD, which can be performed in 96-well plates. Because sphingofungins exert antifungal activitiy as well, we compared the in vitro assay results with an in vivo growth assay using Saccharomyces cerevisiae. The reported experiments showed differences among the assayed sphingofungins, highlighting an increase of activity based on the saturation levels of the polyketide tail.

[89] 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.

Abstract

Synthesis of functionalized δ-hydroxy-β-keto esters using Chan's diene and modified Mukaiyama-aldol reaction conditions. Diastereoselective reduction to syn- and anti-diols and saponification yielded the respective acids. All synthesized compounds were evaluated for their 5-lipoxygenase activity.

[88] 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.

Abstract

We determined the typical volatile emission of fungus comb biomass and Termitomyces nodules, revealing α-pinene, camphene, and d-limonene as the most abundant terpenes. Genome mining of Termitomyces followed by gene expression studies and phylogenetic analysis of putative enzymes related to secondary metabolite production encoded by the genomes uncovered a conserved and specific biosynthetic repertoire across strains. Finally, we proved by heterologous expression and in vitro enzymatic assays that a highly expressed gene sequence encodes a rare bifunctional mono-/sesquiterpene cyclase able to produce the abundant comb volatiles camphene and d-limonene.

[87] 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.

Abstract

Metabolomic analysis of cocultures of Actinomadura sp. RB99 with fungal symbionts of termites allowed for the MS-guided isolation of four unreported madurastatin derivatives, including a siderophore-metal complex thereof.

[86] 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 (18), 722-731.

Abstract

Aromatic prenylated metabolites have important biological roles and activities in all living organisms. Compared to their importance in all domains of life, we know relatively little about their substrate scopes and metabolic functions. Here, we describe a new UbiA-like prenyltransferase (Ptase) Ubi-297 encoded in a conserved operon of several bacterial taxa, including marine Flavobacteria and the genus Sacchromonospora. In silico analysis of Ubi-297 homologs indicated that members of this Ptase group are composed of several transmembrane α-helices and carry a conserved and distinct aspartic-rich Mg2+-binding domain. We heterologously produced UbiA-like Ptases from the bacterial genera Maribacter, Zobellia, and Algoriphagus in Escherichia coli. Investigation of their substrate scope uncovered the preferential farnesylation of quinoline derivatives, such as 8-hydroxyquinoline-2-carboxylic acid (8-HQA) and quinaldic acid. The results of this study provide new insights into the abundance and diversity of Ptases in marine Flavobacteria and beyond.

[85] 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.

Abstract

Herein, we demonstrate the applicability of the 2,5-dimethylpyrrolo unit as a complementary N-protecting group in the highly diastereoselective synthesis of more than 20 different anti-amino alcohols (63–90% yields with up to 20 : 1 dr). Cleavage of the pyrrolo-N-protecting group was accomplished, e.g. in the presence of NH2OH under microwave conditions with yields exceeding 80%. The applicability of the protecting groups was further demonstrated by a short total synthesis of the sphinganine-like natural product clavaminol A. The introduction of the N-pyrrolo protecting group also offers the possibility to analyse product mixtures by NMR measurements due to the absence of conformational isomers, which are otherwise common for N-protecting groups.

[84] Raguž L, Peng CC, Kaiser M, Görls H, Beemelmanns C^* (2022). A modular approach to the antifungal Sphingofungin family: Concise total synthesis of Sphingofungin A and C. Angew Chem Int Ed, e202112616.

Abstract

Sphingofungins are fungal natural products known to inhibit the biosynthesis of sphingolipids which play pivotal roles in various cell functions. Here, we report a short and flexible synthetic approach towards the sphingofungin family. Key step of the synthesis was a decarboxylative cross-coupling reaction of chiral sulfinyl imines with a functionalized tartaric acid derivative, which yielded the core motif of sphingofungins carrying four consecutive stereocenters and a terminal double bond. Subsequent metathesis reaction allowed for the introduction of different side chains of choice resulting in a total of eight sphingofungins, including for the first time sphingofungin C (eight steps from commercially available protected tartaric acid with an overall yield of 6 %) and sphingofungin A (ten steps). All newly synthesized derivatives were tested for their antifungal, cell-proliferative and antiparasitic activity unraveling their structure–activity relations.

2021

[83] Amiri Moghaddam J, Jautzus T, Alanjary M, Beemelmanns C* (2021). Recent highlights of biosynthetic studies on marine natural products. Org Biomol Chem 19(1), 123-140. (Review)

[82] Conlon BH, Gostinčar C, Fricke J, Kreuzenbeck NB, Daniel JM, Schlosser MSL, Peereboom N, Aanen DK, de Beer ZW, Beemelmanns C, Gunde-Cimerman N, Poulsen M (2021). Genome reduction and relaxed selection is associated with the transition to symbiosis in the basidiomycete genus Podaxis. iScience 24(6), 102680.

[81] Guo H, Rischer M, Westermann M, Beemelmanns C* (2021). Two distinct bacterial biofilm components trigger metamorphosis in the colonial hydrozoan Hydractinia echinata. mBio 12(3), e0040121.

[80] Lee SR, Guo H, Yu JS, Park M, Dahse HM, Jung WH, Beemelmanns C*, Kim KH* (2021). Revised structural assignment of azalomycins based on genomic and chemical analysis. Org Chem Front 8, 4791-4798.

[79] Leichnitz D, Peng CC, Raguž L, Rutaganira FUN, Jautzus T, Regestein L, King N, Beemelmanns C* (2021). Structural and functional analysis of bacterial sulfonosphingolipids and rosette-inducing factor 2 (RIF-2) by mass spectrometry-guided isolation and total synthesis. Chemistry, 28(8), e202103883.

[78] Loos D^*, Zhang L, Beemelmanns C, Kurzai O, Panagiotou G* (2021). DAnIEL: A user-friendly web server for fungal ITS amplicon sequencing data. Front Microbiol 12, 720513.

^*corresponding author, # equal contribution