INBioPharm

• Degnes, Kristin Fløgstad; Nordborg, Anna; Nguyen, Giang-Son; Nærdal, Guro Kruge; Heggeset, Tonje Marita Bjerkan & Molesworth, Peter Patrick [Show all 15 contributors for this article] (2025). Discovery of MBL-AB01: a novel antibacterial xanthone antibiotic with high activity against methicillin-resistant Staphylococcus aureus. Applied and Environmental Microbiology. ISSN 0099-2240. p. 1–22. doi: 10.1128/aem.01346-25. Full text in Research Archive Show summary

  Abstract: A novel compound denoted MBL-AB01 was isolated from a marine Actinoalloteichus , which belongs to a rare and underexplored class of Actinobacteria . This work demonstrates that the novel compound MBL-AB01 shows very high activity in vitro against six methicillin-resistant Staphylococcus aureus strains, and high activity against a panel of three other Gram-positive strains, including a vancomycin-resistant Enterococcus faecium . Structure elucidation of the compound revealed that MBL-AB01 is a polycyclic xanthone antibiotic closely related to the bioactive compounds: xantholipin and lysolipin. This class of antibiotics has caught interest due to its unique chemical structure and diverse biological activity. The gene cluster encoding MBL-AB01 production was identified, and the individual genes within the cluster were annotated along with proposed functional roles. The compound was produced by bioreactor fermentations, and significantly higher yields of MBL-AB01 were obtained after classical mutagenesis and fermentation process improvements. Importance: Methicillin-resistant Staphylococcus aureus (MRSA) infections have become a great challenge in hospitals over the last decades, and MRSA is currently one of the six pathogens on the World Health Organization priority list. Here, we demonstrate that the novel antibiotic MBL-AB01 has excellent antibacterial properties against six S. aureus strains, including MRSA. MBL-AB01 belongs to the poorly explored class of polycyclic xanthones, thereby fulfilling innovation criteria for the development of new antibiotics. The compound can be produced in sufficient amounts for early formulation development and pre-clinical trials.

• Kumar, Kanhaiya & Bruheim, Per (2022). Nutrient-depended metabolic switching during batch cultivation of Streptomyces coelicolor explored with absolute quantitative mass spectrometry based metabolite profiling. 3 Biotech. ISSN 2190-572X. 12. doi: 10.1007/s13205-022-03146-x. Full text in Research Archive
• Kumar, Kanhaiya & Bruheim, Per (2022). A comparative study at bioprocess and metabolite levels of superhost strain Streptomyces coelicolor M1152 and its derivative M1581 heterologously expressing chloramphenicol biosynthetic gene cluster. Biotechnology and Bioengineering. ISSN 0006-3592. 119, p. 145–161. doi: 10.1002/bit.27958. Full text in Research Archive
• Kumar, Kanhaiya & Bruheim, Per (2021). Large dependency of intracellular NAD and CoA pools on cultivation conditions in Saccharomyces cerevisiae. BMC Research Notes. 14(1). doi: 10.1186/s13104-021-05783-6. Full text in Research Archive
• Sandoval-Powers, Megan; Králová, Stanislava; Nguyen, Giang-Son; Fawwal, Dorelle V.; Degnes, Kristin Fløgstad & Lewin, Anna [Show all 9 contributors for this article] (2021). Streptomyces poriferorum sp. nov., a novel marine sponge-derived Actinobacteria species expressing anti-MRSA activity. Systematic and Applied Microbiology. ISSN 0723-2020. 44(5). doi: 10.1016/j.syapm.2021.126244. Full text in Research Archive Show summary

  Marine sponges represent a rich source of uncharacterized microbial diversity, and many are host to microorganisms that produce biologically active specialized metabolites. Here, a polyphasic approach was used to characterize two Actinobacteria strains, P01-B04T and P01-F02, that were isolated from the marine sponges Geodia barretti (Bowerbank, 1858) and Antho dichotoma (Esper, 1794), respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strains P01-B04T and P01-F02 are closely related to Streptomyces beijiangensis DSM 41794T, Streptomyces laculatispora NRRL B-24909T, and Streptomyces brevispora NRRL B-24910T. The two strains showed nearly identical 16S rRNA gene sequences (99.93%), and the average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) relatedness values were 99.96% and 99.6%, respectively, suggesting that these strains are affiliated with the same species. Chemotaxonomic and culture characteristics of both strains were also consistent with the genus Streptomyces, while phenotypic properties, genome-based comparisons, and phylogenomic analyses distinguished strains P01-B04T and P01-F02 from their closest phylogenetic relatives. In silico analysis predicted that the 8.9 Mb genome of P01-B04T contains at least 41 biosynthetic gene clusters (BGCs) encoding secondary metabolites, indicating that this strain could express diverse bioactive metabolites; in support of this prediction, this strain expressed antibacterial activity against Gram-positive bacteria including a clinical isolate of methicillin-resistant Staphylococcus aureus (MRSA) EAMC30. Based on these results, the marine sponge-associated isolates represent a novel species of the genus Streptomyces, for which the name Streptomyces poriferorum sp. nov. is proposed, with P01-B04T (=DSM 111306T = CCM 9048T) as the type strain.

• Králová, Stanislava; Sandoval-Powers, Megan; Fawwal, Dorelle V.; Degnes, Kristin Fløgstad; Lewin, Anna & Klinkenberg, Geir [Show all 9 contributors for this article] (2021). Streptomyces tardus sp. nov.: A Slow-Growing Actinobacterium Producing Candicidin, Isolated From Sediments of the Trondheim Fjord. Frontiers in Microbiology. 12. doi: 10.3389/fmicb.2021.714233. Full text in Research Archive Show summary

  Marine environments are home to an extensive number of microorganisms, many of which remain unexplored for taxonomic novelty and functional capabilities. In this study, a slow-growing Streptomyces strain expressing unique genomic and phenotypic characteristics, P38-E01T , was described using a polyphasic taxonomic approach. This strain is part of a collection of over 8,000 marine Actinobacteria isolates collected in the Trondheim fjord of Norway by SINTEF Industry (Trondheim, Norway) and the Norwegian University of Science and Technology (NTNU, Trondheim, Norway). Strain P38-E01T was isolated from the sediments of the Trondheim fjord, and phylogenetic analyses affiliated this strain with the genus Streptomyces, but it was not closely affiliated with other described species. The closest related type strains were Streptomyces daliensis YIM 31724T (98.6%), Streptomyces rimosus subsp. rimosus ATCC 10970T (98.4%), and Streptomyces sclerotialus NRRL ISP-5269T (98.3%). Predominant fatty acids were C16V0 iso, C16V0, and Summed Feature 3, and the predominant respiratory quinones were MK-10(H6), MK-10(H4), and MK9(H4). The main polar lipids were identified as diphosphatidylglycerol, phosphatidylethanolamine, hosphatidylglycerol, and phosphoglycolipid. The whole-cell sugars were glucose, ribose, and in minor amounts, mannose. The cell wall peptidoglycan contained LL-diaminopimelic acid. The draft genome has a size of 6.16 Mb, with a %G C C content of 71.4% and is predicted to contain at least 19 biosynthetic gene clusters encoding diverse secondary metabolites. Strain P38-E01T was found to inhibit the growth of the pathogenic yeast Candida albicans ATCC 90028 and a number of Gram-positive bacterial human and plant pathogens. Metabolites extracted from cultures of P38-E01T were analyzed by mass spectrometry, and it was found that the isolate produced the antifungal compound candicidin. Phenotypic and chemotaxonomic signatures, along with phylogenetic analyses, distinguished isolate P38-E01T from its closest neighbors; thus, this isolate represents a novel species of the genus Streptomyces for which the name Streptomyces tardus sp. nov. (P38-E01T D CCM 9049T D DSM 111582T ) is proposed.

• Ofaim, Shany; Sulheim, Snorre; Almaas, Eivind; Sher, Daniel & Segrè, Daniel (2021). Dynamic Allocation of Carbon Storage and Nutrient-Dependent Exudation in a Revised Genome-Scale Model of Prochlorococcus. Frontiers in Genetics. 12. doi: 10.3389/fgene.2021.586293. Full text in Research Archive Show summary

  Microbial life in the oceans impacts the entire marine ecosystem, global biogeochemistry and climate. The marine cyanobacterium Prochlorococcus, an abundant component of this ecosystem, releases a significant fraction of the carbon fixed through photosynthesis, but the amount, timing and molecular composition of released carbon are still poorly understood. These depend on several factors, including nutrient availability, light intensity and glycogen storage. Here we combine multiple computational approaches to provide insight into carbon storage and exudation in Prochlorococcus. First, with the aid of a new algorithm for recursive filling of metabolic gaps (ReFill), and through substantial manual curation, we extended an existing genome-scale metabolic model of Prochlorococcus MED4. In this revised model (iSO595), we decoupled glycogen biosynthesis/degradation from growth, thus enabling dynamic allocation of carbon storage. In contrast to standard implementations of flux balance modeling, we made use of forced influx of carbon and light into the cell, to recapitulate overflow metabolism due to the decoupling of photosynthesis and carbon fixation from growth during nutrient limitation. By using random sampling in the ensuing flux space, we found that storage of glycogen or exudation of organic acids are favored when the growth is nitrogen limited, while exudation of amino acids becomes more likely when phosphate is the limiting resource. We next used COMETS to simulate day-night cycles and found that the model displays dynamic glycogen allocation and exudation of organic acids. The switch from photosynthesis and glycogen storage to glycogen depletion is associated with a redistribution of fluxes from the Entner–Doudoroff to the Pentose Phosphate pathway. Finally, we show that specific gene knockouts in iSO595 exhibit dynamic anomalies compatible with experimental observations, further demonstrating the value of this model as a tool to probe the metabolic dynamic of Prochlorococcus.

• Bernstein, David B.; Sulheim, Snorre; Almaas, Eivind & Segrè, Daniel (2021). Addressing uncertainty in genome-scale metabolic model reconstruction and analysis. Genome Biology. ISSN 1465-6906. 22, p. 1–22. doi: 10.1186/s13059-021-02289-z. Full text in Research Archive Show summary

  The reconstruction and analysis of genome-scale metabolic models constitutes a powerful systems biology approach, with applications ranging from basic understanding of genotype-phenotype mapping to solving biomedical and environmental problems. However, the biological insight obtained from these models is limited by multiple heterogeneous sources of uncertainty, which are often difficult to quantify. Here we review the major sources of uncertainty and survey existing approaches developed for representing and addressing them. A unified formal characterization of these uncertainties through probabilistic approaches and ensemble modeling will facilitate convergence towards consistent reconstruction pipelines, improved data integration algorithms, and more accurate assessment of predictive capacity.

• Sulheim, Snorre; Fossheim, Fredrik A.; Wentzel, Alexander & Almaas, Eivind (2021). Automatic reconstruction of metabolic pathways from identified biosynthetic gene clusters. BMC Bioinformatics. 22. doi: 10.1186/s12859-021-03985-0. Full text in Research Archive Show summary

  Background A wide range of bioactive compounds is produced by enzymes and enzymatic complexes encoded in biosynthetic gene clusters (BGCs). These BGCs can be identified and functionally annotated based on their DNA sequence. Candidates for further research and development may be prioritized based on properties such as their functional annotation, (dis)similarity to known BGCs, and bioactivity assays. Production of the target compound in the native strain is often not achievable, rendering heterologous expression in an optimized host strain as a promising alternative. Genome-scale metabolic models are frequently used to guide strain development, but large-scale incorporation and testing of heterologous production of complex natural products in this framework is hampered by the amount of manual work required to translate annotated BGCs to metabolic pathways. To this end, we have developed a pipeline for an automated reconstruction of BGC associated metabolic pathways responsible for the synthesis of non-ribosomal peptides and polyketides, two of the dominant classes of bioactive compounds. Results The developed pipeline correctly predicts 72.8% of the metabolic reactions in a detailed evaluation of 8 different BGCs comprising 228 functional domains. By introducing the reconstructed pathways into a genome-scale metabolic model we demonstrate that this level of accuracy is sufficient to make reliable in silico predictions with respect to production rate and gene knockout targets. Furthermore, we apply the pipeline to a large BGC database and reconstruct 943 metabolic pathways. We identify 17 enzymatic reactions using high-throughput assessment of potential knockout targets for increasing the production of any of the associated compounds. However, the targets only provide a relative increase of up to 6% compared to wild-type production rates. Conclusion With this pipeline we pave the way for an extended use of genome-scale metabolic models in strain design of heterologous expression hosts. In this context, we identified generic knockout targets for the increased production of heterologous compounds. However, as the predicted increase is minor for any of the single-reaction knockout targets, these results indicate that more sophisticated strain-engineering strategies are necessary for the development of efficient BGC expression hosts.

• Schulz, Christian; Kumelj, Tjasa; Karlsen, Emil & Almaas, Eivind (2021). Genome-scale metabolic modelling when changes in environmental conditions affect biomass composition. PLoS Computational Biology. ISSN 1553-734X. 17(5). doi: 10.1371/journal.pcbi.1008528. Full text in Research Archive Show summary

  Genome-scale metabolic modeling is an important tool in the study of metabolism by enhancing the collation of knowledge, interpretation of data, and prediction of metabolic capabilities. A frequent assumption in the use of genome-scale models is that the in vivo organism is evolved for optimal growth, where growth is represented by flux through a biomass objective function (BOF). While the specific composition of the BOF is crucial, its formulation is often inherited from similar organisms due to the experimental challenges associated with its proper determination. A cell’s macro-molecular composition is not fixed and it responds to changes in environmental conditions. As a consequence, initiatives for the high-fidelity determination of cellular biomass composition have been launched. Thus, there is a need for a mathematical and computational framework capable of using multiple measurements of cellular biomass composition in different environments. Here, we propose two different computational approaches for directly addressing this challenge: Biomass Trade-off Weighting (BTW) and Higher-dimensional-plane InterPolation (HIP). In lieu of experimental data on biomass composition-variation in response to changing nutrient environment, we assess the properties of BTW and HIP using three hypothetical, yet biologically plausible, BOFs for the Escherichia coli genome-scale metabolic model iML1515. We find that the BTW and HIP formulations have a significant impact on model performance and phenotypes. Furthermore, the BTW method generates larger growth rates in all environments when compared to HIP. Using acetate secretion and the respiratory quotient as proxies for phenotypic changes, we find marked differences between the methods as HIP generates BOFs more similar to a reference BOF than BTW. We conclude that the presented methods constitute a conceptual step in developing genome-scale metabolic modelling approaches capable of addressing the inherent dependence of cellular biomass composition on nutrient environments.

• Kumar, Kanhaiya; Venkatraman, Vishwesh & Bruheim, Per (2021). Adaptation of central metabolite pools to variations in growth rate and cultivation conditions in Saccharomyces cerevisiae. Microbial Cell Factories. 20. doi: 10.1186/s12934-021-01557-8. Full text in Research Archive Show summary

  Background Saccharomyces cerevisiae is a well-known popular model system for basic biological studies and serves as a host organism for the heterologous production of commercially interesting small molecules and proteins. The central metabolism is at the core to provide building blocks and energy to support growth and survival in normal situations as well as during exogenous stresses and forced heterologous protein production. Here, we present a comprehensive study of intracellular central metabolite pool profiling when growing S. cerevisiae on different carbon sources in batch cultivations and at different growth rates in nutrient-limited glucose chemostats. The latest versions of absolute quantitative mass spectrometry-based metabolite profiling methodology were applied to cover glycolytic and pentose phosphate pathway metabolites, tricarboxylic acid cycle (TCA), complete amino acid, and deoxy-/nucleoside phosphate pools. Results Glutamate, glutamine, alanine, and citrate were the four most abundant metabolites for most conditions tested. The amino acid is the dominant metabolite class even though a marked relative reduction compared to the other metabolite classes was observed for nitrogen and phosphate limited chemostats. Interestingly, glycolytic and pentose phosphate pathway (PPP) metabolites display the largest variation among the cultivation conditions while the nucleoside phosphate pools are more stable and vary within a closer concentration window. The overall trends for glucose and nitrogen-limited chemostats were increased metabolite pools with the increasing growth rate. Next, comparing the chosen chemostat reference growth rate (0.12 h−1, approximate one-fourth of maximal unlimited growth rate) illuminates an interesting pattern: almost all pools are lower in nitrogen and phosphate limited conditions compared to glucose limitation, except for the TCA metabolites citrate, isocitrate and α-ketoglutarate. Conclusions This study provides new knowledge-how the central metabolism is adapting to various cultivations conditions and growth rates which is essential for expanding our understanding of cellular metabolism and the development of improved phenotypes in metabolic engineering.

• Sulheim, Snorre; Kumelj, Tjasa; Dissel, Dino van; Salehzadeh-Yazdi, Ali; Du, Chao & Wezel, Gilles P. Van [Show all 10 contributors for this article] (2020). Enzyme-Constrained Models and Omics Analysis of Streptomyces coelicolor Reveal Metabolic Changes that Enhance Heterologous Production. iScience. 23(9). doi: 10.1016/j.isci.2020.101525. Full text in Research Archive Show summary

  Many biosynthetic gene clusters (BGCs) require heterologous expression to realize their genetic potential, including silent and metagenomic BGCs. Although the engineered Streptomyces coelicolor M1152 is a widely used host for heterologous expression of BGCs, a systemic understanding of how its genetic modifications affect the metabolism is lacking and limiting further development. We performed a comparative analysis of M1152 and its ancestor M145, connecting information from proteomics, transcriptomics, and cultivation data into a comprehensive picture of the metabolic differences between these strains. Instrumental to this comparison was the application of an improved consensus genome-scale metabolic model (GEM) of S. coelicolor. Although many metabolic patterns are retained in M1152, we find that this strain suffers from oxidative stress, possibly caused by increased oxidative metabolism. Furthermore, precursor availability is likely not limiting polyketide production, implying that other strategies could be beneficial for further development of S. coelicolor for heterologous production of novel compounds.

• Røst, Lisa Marie; Thorfinnsdottir, Lilja Brekke; Kumar, Kanhaiya; Fuchino, Katsuya; Langørgen, Ida Eide & Bartosova, Zdenka [Show all 8 contributors for this article] (2020). Absolute Quantification of the Central Carbon Metabolome in Eight Commonly Applied Prokaryotic and Eukaryotic Model Systems. Metabolites. 10(74). doi: 10.3390/metabo10020074. Full text in Research Archive Show summary

  Absolute quantification of intracellular metabolite pools is a prerequisite for modeling and in-depth biological interpretation of metabolomics data. It is the final step of an elaborate metabolomics workflow, with challenges associated with all steps—from sampling to quantifying the physicochemically diverse metabolite pool. Chromatographic separation combined with mass spectrometric (MS) detection is the superior platform for high coverage, selective, and sensitive detection of metabolites. Herein, we apply our quantitative MS-metabolomics workflow to measure and present the central carbon metabolome of a panel of commonly applied biological model systems. The workflow includes three chromatographic methods combined with isotope dilution tandem mass spectrometry to allow for absolute quantification of 68 metabolites of glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, and the amino acid and (deoxy) nucleoside pools. The biological model systems; Bacillus subtilis, Saccharomyces cerevisiae, two microalgal species, and four human cell lines were all cultured in commonly applied culture media and sampled in exponential growth phase. Both literature and databases are scarce with comprehensive metabolite datasets, and existing entries range over several orders of magnitude. The workflow and metabolite panel presented herein can be employed to expand the list of reference metabolomes, as encouraged by the metabolomics community, in a continued effort to develop and refine high-quality quantitative metabolomics workflows.

• Røst, Lisa Marie; Darestani, Armaghan Shafaei; Fuchino, Katsuya & Bruheim, Per (2020). Zwitterionic HILIC tandem mass spectrometry with isotope dilution for rapid, sensitive and robust quantification of pyridine nucleotides in biological extracts. Journal of chromatography. B. ISSN 1570-0232. 1144, p. 1–12. doi: 10.1016/j.jchromb.2020.122078. Full text in Research Archive Show summary

  The pyridine nucleotides nicotineamide adenine dinucleotide (NAD) and nicotineamide adenine dinucleotide phosphate (NADP) are conserved coenzymes across all domains of life, and are involved in more than 200 different hydride transfer reactions supporting essential catabolic and anabolic functions. The intracellular levels of these metabolites, and the ratio of their oxidized to reduced forms regulate an extensive network of reactions ranging beyond metabolism. Hence, monitoring their intracellular levels provides information about, but not limited to, the metabolic state of a cell or tissue. Interconversion between oxidized and reduced forms, varying pH liability and varying intracellular concentrations of the different species leaves absolute quantification of the pyridine nucleotides analytically challenging. These polar metabolites are poorly retained on conventional reverseed-phase stationary phases without ion-pair reagents that contaminates the LC-system. Herein we demonstrate that zwitterionic HILIC-tandem mass spectroemtry can be applied to successfully resolve the pyridine nucleotides in biological extracts in a fast, robust and highly sensitive way. The presented method applies isotope dilution to compensate potential loss of these labile metabolites and is validated for low, medium and high biomass samples of two popular biological model systems; Escherichia coli and the human cell line JJN-3. High stability and rapid sample preparation without solvent removal allows for long sequence runs, making this method ideal for high-throughput analysis of biological extracts.

• Kumelj, Tjasa; Sulheim, Snorre; Wentzel, Alexander & Almaas, Eivind (2019). Predicting strain engineering strategies using iKS1317: a genome-scale metabolic model of Streptomyces coelicolor. Biotechnology Journal. ISSN 1860-6768. 14(4). doi: 10.1002/biot.201800180. Full text in Research Archive Show summary

  Streptomyces coelicolor is a model organism for the Actinobacteria, a phylum known to produce an extensive range of different bioactive compounds that include antibiotics currently used in the clinic. Biosynthetic gene clusters discovered in genomes of other Actinobacteria can be transferred to and expressed in S. coelicolor, making it a factory for heterologous production of secondary metabolites. Genome‐scale metabolic reconstructions have successfully been used in several biotechnology applications to facilitate the over‐production of target metabolites. Here, the authors present iKS1317, the most comprehensive and accurate reconstructed genome‐scale metabolic model (GEM) for S. coelicolor. The model reconstruction is based on previous models, publicly available databases, and published literature and includes 1317 genes, 2119 reactions, and 1581 metabolites. It correctly predicts wild‐type growth in 96.5% of the evaluated growth environments and gene knockout predictions in 78.4% when comparing with observed mutant growth phenotypes, with a total accuracy of 83.3%. However, using a minimal nutrient environment for the gene knockout predictions, iKS1317 has an accuracy of 87.1% in predicting mutant growth phenotypes. Furthermore, we used iKS1317 and existing strain design algorithms to suggest robust gene‐knockout strategies to increase the production of acetyl‐CoA. Since acetyl‐CoA is the most important precursor for polyketide antibiotics, the suggested strategies may be implemented in vivo to improve the function of S. coelicolor as a heterologous expression host.

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• Wentzel, Alexander (2025). Autonomous Marine Biodiversity Mapping and Bioprospecting. Full text in Research Archive
• Wentzel, Alexander (2025). Autonomous Marine Biodiversity Mapping and Bioprospecting. Full text in Research Archive
• Stankey, Robb; Johnson, Don; Montaser, R.; Caesar, L.; Sandoval-Powers, Megan & MacDonald, J. [Show all 13 contributors for this article] (2023). New tools for targeted cloning and over-expression of biosynthetic gene clusters. Full text in Research Archive
• Nguyen, Giang-Son; Le, Simone Balzer; Aune, Ingvild Haugnes; Nærdal, Ingemar; Heggeset, Tonje Marita Bjerkan & Bartolomeo, Francesca Di [Show all 12 contributors for this article] (2023). Digital bioprospecting for exploring biodiversity and discovering novel bioactive compounds and industrial enzymes. Full text in Research Archive
• Nguyen, Giang-Son; Le, Simone Balzer; Aune, Ingvild Haugnes; Nærdal, Ingemar; Heggeset, Tonje Marita Bjerkan & Bartolomeo, Francesca Di [Show all 12 contributors for this article] (2023). Digital bioprospecting for exploring biodiversity and discovering novel bioactive compounds and industrial enzymes. Full text in Research Archive
• Stankey, Robb; Johnson, Don; Montaser, R.; Caesar, L.; Sandoval-Powers, Megan & MacDonald, J. [Show all 13 contributors for this article] (2022). New Tools For Targeted Cloning And Over Expression Of Biosynthetic Gene Clusters. Full text in Research Archive
• Nguyen, Giang-Son (2022). Hva er bioaktive molekyler og hvor finner vi dem? Full text in Research Archive
• Nguyen, Giang-Son; Le, Simone Balzer; Jønsson, Malene; Aune, Ingvild; Cordas, Cristina M. & Moura, José J. G. [Show all 17 contributors for this article] (2022). Bioinformatics at SINTEF Biotechnology. Full text in Research Archive
• Wentzel, Alexander (2022). New Natural Products From Marine Actinobacteria and Microbiomes. Full text in Research Archive
• Liles, Mark R.; Stankey, Robb; Johnson, Don; Sandoval-Powers, Megan; MacDonald, J. & Brumm, Phil [Show all 8 contributors for this article] (2022). Soil Microorganisms and Metagenomes as Sources of Anti-infective Metabolites. Full text in Research Archive
• Wentzel, Alexander (2022). New Natural Products From Marine Actinobacteria and Microbiomes. Full text in Research Archive
• Sulheim, Snorre; Kumelj, Tjasa; Dissel, Dino van; Salehzadeh-Yazdi, Ali; Du, Chao & Wezel, Gilles P. Van [Show all 10 contributors for this article] (2021). A systems comparison of Streptomyces coelicolor M1152 and M145 reveals major metabolic rewiring. Full text in Research Archive
• Fawwal, Dorelle V.; Sandoval-Powers, Megan; Králová, Stanislava; Wentzel, Alexander & Liles, Mark R. (2021). Novel Streptomyces species from marine sponges produce metabolites that kill methicillin-resistant Staphylococcus aureus (MRSA). Full text in Research Archive
• Stankey, Robb; Johnson, Don; Wozniak, K.; Montaser, R.; Kelleher, N. & Pereira, A [Show all 14 contributors for this article] (2021). New tools for targeted cloning and over expression of biosynthetic gene clusters. Full text in Research Archive
• Stankey, Robb; Johnson, Don; Wozniak, K.; Montaser, R.; Kelleher, N. L. & Pereira, A [Show all 14 contributors for this article] (2020). New Tools For Targeted Cloning And Over Expression Of Biosynthetic Gene Clusters. Full text in Research Archive
• Wentzel, Alexander (2020). INBioPharm: New drugs to combat antibiotic resistance. Full text in Research Archive
• Wentzel, Alexander (2020). Expanding the (meta)genomics toolbox for novel enzyme and bioactive compound discovery and production. Full text in Research Archive
• Wentzel, Alexander (2020). INBioPharm: Integrated Novel Natural Product Discovery and Production Platform for Accelerated Biopharmaceutical Innovation from Microbial Biodiversity. Full text in Research Archive
• Wentzel, Alexander (2020). Bioinformatics for Metagenomics - Introduction to 3 seminar presentations. Full text in Research Archive
• Almaas, Eivind (2020). Stories of network analysis: Cellular metabolism to COVID-19. Full text in Research Archive
• Wentzel, Alexander; Nguyen, Giang-Son & Degnes, Kristin Fløgstad (2020). Sequence- and function-based bioprospecting of Norwegian microbial biodiversity for novel natural products. Full text in Research Archive
• Sulheim, Snorre; Kumelj, Tjasa; Salehzadeh-Yazdi, Ali; Dissel, Dino van; Chao, Du & Nieselt, Kay [Show all 9 contributors for this article] (2019). An enzyme-constrained genome-scale metabolic model of Streptomyces coelicolor reveals global effects of gene cluster deletion and rpoB mutation. Full text in Research Archive
• Stankey, Robb; Johnson, Don; Wozniak, Katherine; Pereira, Alinne; Sandoval-Powers, Megan & MacDonald, Joyanne [Show all 12 contributors for this article] (2019). New Tools For Targeted Cloning And Over Expression Of Biosynthetic Gene Clusters. Full text in Research Archive
• Nguyen, Giang-Son; Lewin, Anna; Degnes, Kristin Fløgstad; Klinkenberg, Geir; Sletta, Håvard & Ellingsen, Trond Erling [Show all 14 contributors for this article] (2019). Exploring the great potential of an Actinobacteria strain collection from Trondheim fjord for the discovery of novel antibiotics and enzyme systems for biomass degradation. Full text in Research Archive
• Wentzel, Alexander (2019). Metabolomics approaches in the INBioPharm project. Full text in Research Archive
• Wentzel, Alexander; Lewin, Anna; Nordborg, Anna; Nguyen, Giang-Son; Degnes, Kristin Fløgstad & Sulheim, Snorre [Show all 34 contributors for this article] (2019). Expanding the (meta)genomics toolbox for the discovery and production of novel natural products from microbial resources. Full text in Research Archive Show summary

  Bioactive chemicals produced by microorganisms isolated from nature have been the source of most antibiotics in medical use today. However, many antibiotics are currently losing their potency due to rapidly spreading antibiotic resistance among pathogenic bacteria. Coincidently, very few new antibiotics have recently reached the market, essentially due to a very high re-discovery rate, compromising interest of major pharmaceutical companies to invest in the field. New strategies and technologies that allow targeted discovery of novel bioactive chemistry from yet underexplored natural resources may secure treatment options of life-threatening bacterial infections in the future. In the joint frame of European research project SYSTERACT and Norwegian national research project INBioPharm, we are developing and integrating a suite of new technologies that will allow for a more efficient discovery of novel bioactive natural products with improved prospects for clinical use. A unique national collection of marine microorganisms at SINTEF/NTNU, Norway, is used as a platform for the development of bioinformatics, molecular biology, analytical, screening, and integrated systems biology methods to more efficiently access and exploit the huge potential of microorganisms for natural product biosynthesis. Central to this effort are the development of high throughput technologies for cloning (meta)genome derived biosynthetic gene clusters (BGCs) and their transfer between species for heterologous expression. Strains of the model Actinobacterium Streptomyces coelicolor are further developed into improved microbial cell factories to heterologously produce diverse bioactive compounds in amounts needed for structural and functional evaluation. Unprecedented systems biology understanding of S. coelicolor is being combined with morphology engineering and improved (de )regulation and precursor supply to accelerate bioactive compound discovery efforts. The new BGC cloning, transfer, and expression technologies provide access to both cryptic gene clusters of cultivable strains and the vast resources of otherwise inaccessible BGC functions from the vast majority of bacteria that cannot readily be cultivated in the laboratory. The work presented was performed in the project INBioPharm funded by the Research Council of Norway (grant no. 248885) and the SYSTERACT project by ERASysAPP partner funding agencies in Norway, Germany, Netherlands and Sweden.

• Kumar, Kanhaiya; Wentzel, Alexander & Bruheim, Per (2019). Deciphering the carbon distribution in metabolic pathways during antibiotic production by Streptomyces superhost strains using 13C-isotope-labeling experiments. Full text in Research Archive
• Kumar, Kanhaiya; Wentzel, Alexander & Bruheim, Per (2019). Carbon distribution within metabolic pathways during antibiotic production by Streptomyces superhost strains. Full text in Research Archive
• Kumar, Kanhaiya; Wentzel, Alexander & Bruheim, Per (2019). Studying the metabolism of Streptomyces coelicolor during antibiotic production in submerged batch fermentations. Full text in Research Archive
• Wentzel, Alexander; Lewin, Anna; Nordborg, Anna; Nguyen, Giang-Son; Degnes, Kristin Fløgstad & Sulheim, Snorre [Show all 34 contributors for this article] (2019). Expanding the (meta)genomics toolbox for the discovery and production of novel natural products from microbial resources. Full text in Research Archive Show summary

  Bioactive chemicals produced by microorganisms isolated from nature have been the source of most antibiotics in medical use today. However, many antibiotics are currently losing their potency due to rapidly spreading antibiotic resistance among pathogenic bacteria. Coincidently, very few new antibiotics have recently reached the market, essentially due to a very high re-discovery rate, compromising interest of major pharmaceutical companies to invest in the field. New strategies and technologies that allow targeted discovery of novel bioactive chemistry from yet underexplored natural resources may secure treatment options of life-threatening bacterial infections in the future. In the joint frame of European research project SYSTERACT and Norwegian national research project INBioPharm, we are developing and integrating a suite of new technologies that will allow for a more efficient discovery of novel bioactive natural products with improved prospects for clinical use. A unique national collection of marine microorganisms at SINTEF/NTNU, Norway, is used as a platform for the development of bioinformatics, molecular biology, analytical, screening, and integrated systems biology methods to more efficiently access and exploit the huge potential of microorganisms for natural product biosynthesis. Central to this effort are the development of high throughput technologies for cloning (meta)genome derived biosynthetic gene clusters (BGCs) and their transfer between species for heterologous expression. Strains of the model Actinobacterium Streptomyces coelicolor are further developed into improved microbial cell factories to heterologously produce diverse bioactive compounds in amounts needed for structural and functional evaluation. Unprecedented systems biology understanding of S. coelicolor is being combined with morphology engineering and improved (de )regulation and precursor supply to accelerate bioactive compound discovery efforts. The new BGC cloning, transfer, and expression technologies provide access to both cryptic gene clusters of cultivable strains and the vast resources of otherwise inaccessible BGC functions from the vast majority of bacteria that cannot readily be cultivated in the laboratory. The work presented was performed in the project INBioPharm funded by the Research Council of Norway (grant no. 248885) and the SYSTERACT project by ERASysAPP partner funding agencies in Norway, Germany, Netherlands and Sweden.

• Kumar, Kanhaiya; Wentzel, Alexander & Bruheim, Per (2019). Studying the metabolism of Streptomyces coelicolor during antibiotic production using 13C-isotope-labeling experiments. Full text in Research Archive
• Sulheim, Snorre; Kumelj, Tjasa; Sletta, Håvard; Wentzel, Alexander & Almaas, Eivind (2018). Predicting phenotypes using iKS1317: a genome-scale metabolic model of Streptomyces coelicolor. Full text in Research Archive
• Sulheim, Snorre; Degnes, Kristin Fløgstad; Nguyen, Giang-Son; Wentzel, Alexander & Almaas, Eivind (2018). A network approach to efficient drug discovery. Full text in Research Archive
• Mead, David A.; Pereira, Alinne; Sandoval, Megan; Zhou, Jinglie; Monsma, Scott & Degnes, Kristin Fløgstad [Show all 9 contributors for this article] (2018). Mining and Expressing Biosynthetic Gene Clusters from Soil Metagenomes. Full text in Research Archive
• Kumar, Kanhaiya; Wentzel, Alexander & Bruheim, Per (2018). Intracellular metabolite profiling of Streptomyces coelicolor A3(2) in nutrient stressed batch fermentation for antibiotic production. Full text in Research Archive Show summary

  One task of the Centre for Digital Life Norway project INBioPharm is to develop optimized Streptomyces Superhost strains for heterologous production of new bioactive compounds by using Systems and Synthetic Biology approaches. One important experimental input to this task will be the generation of high-resolution quantitative metabolite profiles of the Streptomyces host production strains. In this study, wild type strain M145 of Streptomyces coelicolor A3(2), its mutant strain M1146 with the deleted biosynthetic gene clusters producing actinorhodin, undecylprodigiosin, CPK and CDA and M1152 having introduced point mutation into rpoB, were used for complete profiling of the intracellular primary metabolite pools. Intracellular metabolite pools were quantified using several MS/MS based methods; i.e. two UPLC-MS/MS methods for amino acids and organic acids, a capIC-MS/MS method for nucleotides, sugar phosphate and other phosphometabolites. Fermentation data were used for mass balance, growth and production kinetics analysis. SSBM medium coupled with either L-glutamate or phosphate limitation triggered antibiotics production. Contrary to phosphate limitation, nitrogen (L-glutamate) limitation triggered the stringent stress response as observed by a sharp decline in the CO2 production and biomass concentration. The consumption of L-glutamate in broth reflected in the depletion of intracellular L-glutamate and the corresponding decrease in intracellular glutamine and α-Ketoglutarate, an entry point of L-glutamate into metabolic pathway. 6-phosphogluconic acid, first metabolite of pentose phosphate pathway (PPP) was found to rise with biomass generation showing increased PPP activity during growth phase. A higher activity of PPP ensures a continued supply of NADPH and precursor metabolites for highly dividing cells. The energy charge ratio was higher during mid-exponential and antibiotic production phase in comparison of stationary phase.

• Kumar, Kanhaiya; Wentzel, Alexander & Bruheim, Per (2018). Intracellular metabolite profiling of Streptomyces coelicolor A3(2) during antibiotic production in nutrient stressed batch fermentation. Full text in Research Archive
• Degnes, Kristin Fløgstad; Nguyen, Giang-Son; Klinkenberg, Geir; Sletta, Håvard; Lewin, Anna & Nordborg, Anna [Show all 13 contributors for this article] (2018). Heterologous expression of actinobacterial biosynthetic gene clusters and identification of novel bioactive compounds by multi-omics networking. Full text in Research Archive
• Nguyen, Giang-Son; Lewin, Anna; Degnes, Kristin Fløgstad; Klinkenberg, Geir; Sletta, Håvard & Ellingsen, Trond E [Show all 13 contributors for this article] (2018). Actinobacteria from the Trondheim fjord: a promising source of novel bioactive compounds and redox enzyme systems for the biocatalytic conversion of lignocellulose. Full text in Research Archive
• Degnes, Kristin Fløgstad; Nguyen, Giang-Son; Sulheim, Snorre; Klinkenberg, Geir; Sletta, Håvard & Lewin, Anna [Show all 15 contributors for this article] (2018). Novel insights into the natural product potential of a marine Actinobacteria strain collection by combining classical and genomics-based bioprospecting. Full text in Research Archive
• Sulheim, Snorre; Kumelj, Tjasa; Wentzel, Alexander & Almaas, Eivind (2017). A genome-scale metabolic model for Streptomyces coelicolor. Full text in Research Archive
• Sulheim, Snorre; Kumelj, Tjasa; Wentzel, Alexander & Almaas, Eivind (2017). Extended GEM of Streptomyces coelicolor for production of secondary metabolites. Full text in Research Archive
• Wentzel, Alexander; Lewin, Anna; Nordborg, Anna; Nguyen, Giang-Son; Degnes, Kristin Fløgstad & Sulheim, Snorre [Show all 15 contributors for this article] (2017). New bioactive compounds from environmental microbial resources by an integrated functional (meta)genomics approach. Full text in Research Archive
• Nguyen, Giang-Son; Lewin, Anna; Heggeset, Tonje Marita Bjerkan; Degnes, Kristin Fløgstad; Klinkenberg, Geir & Sletta, Håvard [Show all 14 contributors for this article] (2017). Genome sequencing and taxonomic and functional evaluation of 1000 marine Actinobacteria isolates from the Trondheim fjord. Full text in Research Archive
• Wentzel, Alexander; Lewin, Anna; Nordborg, Anna; Nguyen, Giang-Son; Degnes, Kristin Fløgstad & Sulheim, Snorre [Show all 15 contributors for this article] (2017). New bioactive compounds from environmental microbial resources by an integrated functional (meta)genomics approach. Full text in Research Archive
• Sandoval, Megan; Nasrin, S; Lewin, Anna; Wentzel, Alexander; Mead, David A. & Liles, Mark R. (2017). Culture-independent and -dependent characterization and heterologous expression of biosynthetic gene clusters derived from Actinobacteria. Full text in Research Archive
• Sulheim, Snorre; Kumelj, Tjasa; Wentzel, Alexander & Almaas, Eivind (2017). A genome-scale metabolic model for Streptomyces coelicolor. Full text in Research Archive
• Sulheim, Snorre; Kumelj, Tjasa; Wentzel, Alexander & Almaas, Eivind (2017). A genome-scale metabolic model for Streptomyces coelicolor. Full text in Research Archive
• Sulheim, Snorre; Kumelj, Tjasa; Wentzel, Alexander & Almaas, Eivind (2017). A genome-scale metabolic model for Streptomyces coelicolor. Full text in Research Archive
• Kumelj, Tjasa; Sulheim, Snorre; Wentzel, Alexander & Almaas, Eivind (2017). A genome-scale metabolic model for Streptomyces coelicolor. Full text in Research Archive
• Kumelj, Tjasa; Sulheim, Snorre; Wentzel, Alexander & Almaas, Eivind (2017). Extended GEM of Streptomyces coelicolor for production of secondary metabolites. Full text in Research Archive
• Sulheim, Snorre; Almaas, Eivind & Kumelj, Tjasa (2017). A genome-scale metabolic reconstruction of S. coelicolor. Full text in Research Archive
• Wentzel, Alexander; Lewin, Anna; Nordborg, Anna; Nguyen, Giang-Son; Degnes, Kristin Fløgstad & Sulheim, Snorre [Show all 15 contributors for this article] (2017). New bioactive compounds from environmental microbial resources by an integrated functional (meta)genomics approach. Full text in Research Archive
• Wentzel, Alexander; Lewin, Anna; Nordborg, Anna; Nguyen, Giang-Son; Degnes, Kristin Fløgstad & Sulheim, Snorre [Show all 15 contributors for this article] (2017). New bioactive compounds from environmental microbial resources by an integrated functional (meta)genomics approach. Full text in Research Archive
• Heggeset, Tonje Marita Bjerkan; Lewin, Anna; Nguyen, Giang-Son; Nordborg, Anna; Degnes, Kristin Fløgstad & Sletta, Håvard [Show all 11 contributors for this article] (2016). INBioPharm - Integrated Novel Natural Product Discovery and Production Platform for Accelerated Biopharmaceutical Innovation from Microbial Biodiversity. Full text in Research Archive
• Wentzel, Alexander (2016). INBioPharm-Integrated Novel Natural Product Discovery and Production Platform for Accelerated Biopharmaceutical Innovation from Microbial Biodiversity. Full text in Research Archive
• Wentzel, Alexander (2016). INBioPharm-Integrated Novel Natural Product Discovery and Production Platform for Accelerated Biopharmaceutical Innovation from Microbial Biodiversity. Full text in Research Archive
• Wentzel, Alexander (2016). Mikrober fra Trondheimsfjorden som kilde for nye medisiner. Full text in Research Archive
• Wentzel, Alexander (2015). Digitalt liv-prosjekter. [Journal]. Nbs-nytt . Full text in Research Archive
• Tønseth, Svein & Wentzel, Alexander (2015). Bakterier fra havet inn i kampen mot kreft og infeksjoner. [Internet]. Gemini.no. Full text in Research Archive
• Tønseth, Svein & Wentzel, Alexander (2015). Bakterier fra havet inn i kampen mot kreft og infeksjoner. [Internet]. forskning.no. Full text in Research Archive
• Wentzel, Alexander (2015). INBioPharm-Integrated Novel Natural Product Discovery and Production Platform for Accelerated Biopharmaceutical Innovation from Microbial Biodiversity. Full text in Research Archive
• Wentzel, Alexander (2015). INBioPharm-Integrated Novel Natural Product Discovery and Production Platform for Accelerated Biopharmaceutical Innovation from Microbial Biodiversity. Full text in Research Archive

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