• Actinobacteria Isolated from an Underground Lake and Moonmilk Speleothem from the Biggest Conglomeratic Karstic Cave in Siberia as Sources of Novel Biologically Active Compounds.

      Axenov-Gibanov, Denis V; Voytsekhovskaya, Irina V; Tokovenko, Bogdan T; Protasov, Eugeniy S; Gamaiunov, Stanislav V; Rebets, Yuriy V; Luzhetskyy, Andriy N; Timofeyev, Maxim A; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrucken, Germany, 3 Universität des Saarlandes–Pharmazeutische Biotechnologie, Saarbrucken, Germany. (2016)
      Actinobacteria isolated from unstudied ecosystems are one of the most interesting and promising sources of novel biologically active compounds. Cave ecosystems are unusual and rarely studied. Here, we report the isolation and characterization of ten new actinobacteria strains isolated from an ancient underground lake and moonmilk speleothem from the biggest conglomeratic karstic cave in Siberia with a focus on the biological activity of the obtained strains and the metabolite dereplication of one active strain. Streptomyces genera isolates from moonmilk speleothem demonstrated antibacterial and antifungal activities. Some of the strains were able to inhibit the growth of pathogenic Candida albicans.
    • Characterization of Sigma Factor Genes in streptomyces lividans TK24 Using a Genomic Library-Based Approach for Multiple Gene Deletions.

      Rebets, Yuriy; Tsolis, Konstantinos C; Guðmundsdóttir, Elísabet Eik; Koepff, Joachim; Wawiernia, Beata; Busche, Tobias; Bleidt, Arne; Horbal, Liliya; Myronovskyi, Maksym; Ahmed, Yousra; et al. (Frontiers, 2018-01-01)
      Alternative sigma factors control numerous aspects of bacterial life, including adaptation to physiological stresses, morphological development, persistence states and virulence. This is especially true for the physiologically complex actinobacteria. Here we report the development of a robust gene deletions system for Streptomyces lividans TK24 based on a BAC library combined with the λ-Red recombination technique. The developed system was validated by systematically deleting the most highly expressed genes encoding alternative sigma factors and several other regulatory genes within the chromosome of S. lividans TK24. To demonstrate the possibility of large scale genomic manipulations, the major part of the undecylprodigiosin gene cluster was deleted as well. The resulting mutant strains were characterized in terms of morphology, growth parameters, secondary metabolites production and response to thiol-oxidation and cell-wall stresses. Deletion of SLIV_12645 gene encoding S. coelicolor SigR1 ortholog has the most prominent phenotypic effect, resulted in overproduction of actinorhodin and coelichelin P1 and increased sensitivity to diamide. The secreted proteome analysis of SLIV_12645 mutant revealed SigR1 influence on trafficking of proteins involved in cell wall biogenesis and refactoring. The reported here gene deletion system will further facilitate work on S. lividans strain improvement as a host for either secondary metabolites or protein production and will contribute to basic research in streptomycetes physiology, morphological development, secondary metabolism. On the other hand, the systematic deletion of sigma factors encoding genes demonstrates the complexity and conservation of regulatory processes conducted by sigma factors in streptomycetes
    • Chromosomal position effect influences the heterologous expression of genes and biosynthetic gene clusters in Streptomyces albus J1074.

      Bilyk, Bohdan; Horbal, Liliya; Luzhetskyy, Andriy N; Helmholz-Institut für pharmazeutische Forschung , Josef-Schneider-Straße2,97080 Würzburg, Germany. (2017-01-04)
      Efforts to construct the Streptomyces host strain with enhanced yields of heterologous product have focussed mostly on engineering of primary metabolism and/or the deletion of endogenous biosynthetic gene clusters. However, other factors, such as chromosome compactization, have been shown to have a significant influence on gene expression levels in bacteria and fungi. The expression of genes and biosynthetic gene clusters may vary significantly depending on their location within the chromosome. Little is known about the position effect in actinomycetes, which are important producers of various industrially relevant bioactive molecules.
    • Cloning and Heterologous Expression of the Grecocycline Biosynthetic Gene Cluster.

      Bilyk, Oksana; Sekurova, Olga N; Zotchev, Sergey B; Luzhetskyy, Andriy N; Helmholtz Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany. (2016)
      Transformation-associated recombination (TAR) in yeast is a rapid and inexpensive method for cloning and assembly of large DNA fragments, which relies on natural homologous recombination. Two vectors, based on p15a and F-factor replicons that can be maintained in yeast, E. coli and streptomycetes have been constructed. These vectors have been successfully employed for assembly of the grecocycline biosynthetic gene cluster from Streptomyces sp. Acta 1362. Fragments of the cluster were obtained by PCR and transformed together with the "capture" vector into the yeast cells, yielding a construct carrying the entire gene cluster. The obtained construct was heterologously expressed in S. albus J1074, yielding several grecocycline congeners. Grecocyclines have unique structural moieties such as a dissacharide side chain, an additional amino sugar at the C-5 position and a thiol group. Enzymes from this pathway may be used for the derivatization of known active angucyclines in order to improve their desired biological properties.
    • Complete Draft Genome Sequence of the Actinobacterium Nocardiopsis sinuspersici UTMC102 (DSM 45277(T)), Which Produces Serine Protease.

      Tokovenko, Bogdan; Rückert, Christian; Kalinowski, Jörn; Mohammadipanah, Fatemeh; Wink, Joachim; Rosenkränzer, Birgit; Myronovskyi, Maksym; Luzhetskyy, Andriy N; Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany. (2017-05-18)
      The genome sequence of alkalohalophilic actinobacterium Nocardiopsis sinuspersici UTMC102 is provided. N. sinuspersici UTMC102 produces a highly active serine alkaline protease, and contains at least 11 gene clusters encoding the biosynthesis of secondary metabolites. The N. sinuspersici UTMC102 genome was assembled into a single chromosomal scaffold.
    • Complete genome sequence of producer of the glycopeptide antibiotic Aculeximycin Kutzneria albida DSM 43870T, a representative of minor genus of Pseudonocardiaceae

      Rebets, Yuriy; Tokovenko, Bogdan; Lushchyk, Igor; Rückert, Christian; Zaburannyi, Nestor; Bechthold, Andreas; Kalinowski, Jörn; Luzhetskyy, Andriy N (2014-10-10)
      Abstract Background Kutzneria is a representative of a rarely observed genus of the family Pseudonocardiaceae. Kutzneria species were initially placed in the Streptosporangiaceae genus and later reconsidered to be an independent genus of the Pseudonocardiaceae. Kutzneria albida is one of the eight known members of the genus. This strain is a unique producer of the glycosylated polyole macrolide aculeximycin which is active against both bacteria and fungi. Kutzneria albida genome sequencing and analysis allow a deeper understanding of evolution of this genus of Pseudonocardiaceae, provide new insight in the phylogeny of the genus, as well as decipher the hidden secondary metabolic potential of these rare actinobacteria. Results To explore the biosynthetic potential of Kutzneria albida to its full extent, the complete genome was sequenced. With a size of 9,874,926 bp, coding for 8,822 genes, it stands alongside other Pseudonocardiaceae with large circular genomes. Genome analysis revealed 46 gene clusters potentially encoding secondary metabolite biosynthesis pathways. Two large genomic islands were identified, containing regions most enriched with secondary metabolism gene clusters. Large parts of this secondary metabolism “clustome” are dedicated to siderophores production. Conclusions Kutzneria albida is the first species of the genus Kutzneria with a completely sequenced genome. Genome sequencing allowed identifying the gene cluster responsible for the biosynthesis of aculeximycin, one of the largest known oligosaccharide-macrolide antibiotics. Moreover, the genome revealed 45 additional putative secondary metabolite gene clusters, suggesting a huge biosynthetic potential, which makes Kutzneria albida a very rich source of natural products. Comparison of the Kutzneria albida genome to genomes of other actinobacteria clearly shows its close relations with Pseudonocardiaceae in line with the taxonomic position of the genus.
    • Complete genome sequence of producer of the glycopeptide antibiotic Aculeximycin Kutzneria albida DSM 43870T, a representative of minor genus of Pseudonocardiaceae.

      Rebets, Yuriy; Tokovenko, Bogdan; Lushchyk, Igor; Rückert, Christian; Zaburannyi, Nestor; Bechthold, Andreas; Kalinowski, Jörn; Luzhetskyy, Andriy N; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS);Saarland University, Building A4.1, 66123 Saarbruecken, Germany. (2014)
      Kutzneria is a representative of a rarely observed genus of the family Pseudonocardiaceae. Kutzneria species were initially placed in the Streptosporangiaceae genus and later reconsidered to be an independent genus of the Pseudonocardiaceae. Kutzneria albida is one of the eight known members of the genus. This strain is a unique producer of the glycosylated polyole macrolide aculeximycin which is active against both bacteria and fungi. Kutzneria albida genome sequencing and analysis allow a deeper understanding of evolution of this genus of Pseudonocardiaceae, provide new insight in the phylogeny of the genus, as well as decipher the hidden secondary metabolic potential of these rare actinobacteria.
    • Development of a Biosensor Concept to Detect the Production of Cluster-Specific Secondary Metabolites.

      Sun, Yi-Qian; Busche, Tobias; Rückert, Christian; Paulus, Constanze; Rebets, Yuriy; Novakova, Renata; Kalinowski, Jörn; Luzhetskyy, Andriy N; Kormanec, Jan; Sekurova, Olga N; et al. (ACS Publications, 2017-06-16)
      Genome mining of actinomycete bacteria aims at the discovery of novel bioactive secondary metabolites that can be developed into drugs. A new repressor-based biosensor to detect activated secondary metabolite biosynthesis gene clusters in Streptomyces was developed. Biosynthetic gene clusters for undecylprodigiosin and coelimycin in the genome of Streptomyces lividans TK24, which encoded TetR-like repressors and appeared to be almost “silent” based on the RNA-seq data, were chosen for the proof-of-principle studies. The bpsA reporter gene for indigoidine synthetase was placed under control of the promotor/operator regions presumed to be controlled by the cluster-associated TetR-like repressors. While the biosensor for undecylprodigiosin turned out to be nonfunctional, the coelimycin biosensor was shown to perform as expected, turning on biosynthesis of indigoidine in response to the concomitant production of coelimycin. The developed reporter system concept can be applied to those cryptic gene clusters that encode metabolite-sensing repressors to speed up discovery of novel bioactive compounds in Streptomyces.
    • Draft Genome Sequence of Streptomyces sp. Strain IB2014011-1, Isolated from Trichoptera sp. Larvae of Lake Baikal.

      Axenov-Gribanov, Denis V; Tokovenko, Bogdan T; Rebets, Yuriy V; Voytsekhovskaya, Irina V; Shatilina, Zhanna M; Protasov, Eugenii S; Luzhetskyy, Andriy N; Timofeyev, Maxim A; Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany. (2017-04-27)
      Unique ecosystems with specific environmental conditions have been proven to be a promising source for isolation of new actinobacterial strains. Ancient Lake Baikal is one of the greatest examples of an ecosystem with high species biodiversity and endemicity caused by long-lasting isolated evolution and stable environmental conditions. Herein we report the draft genome sequence of Streptomyces sp. strain IB2014011-1, which was isolated from insect Trichoptera sp. larvae collected at the bottom of Lake Baikal.
    • Dual control system - A novel scaffolding architecture of an inducible regulatory device for the precise regulation of gene expression.

      Horbal, L; Luzhetskyy, Andriy N; Helmholtz Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany. (2016-09)
      Here, we present a novel scaffolding architecture of an inducible regulatory device. This dual control system is completely silent in the off stage and is coupled to the regulation of gene expression at both the transcriptional and translational levels. This system also functions as an AND gate. We demonstrated the effectiveness of the cumate-riboswitch dual control system for the control of pamamycin production in Streptomyces albus. Placing the cre recombinase gene under the control of this system permitted the construction of synthetic devices with non-volatile memory that sense the signal and respond by altering DNA at the chromosomal level, thereby producing changes that are heritable. In addition, we present a library of synthetic inducible promoters based on the previously described cumate switch. With only one inducer and different promoters, we demonstrate that simultaneous modulation of the expression of several genes to different levels in various operons is possible. Because all modules of the AND gates are functional in bacteria other than Streptomyces, we anticipate that these regulatory devices can be used to control gene expression in other Actinobacteria. The features described in this study make these systems promising tools for metabolic engineering and biotechnology in Actinobacteria.
    • Endophytic Streptomyces in the traditional medicinal plant Arnica montana L.: secondary metabolites and biological activity.

      Wardecki, Tina; Brötz, Elke; De Ford, Christian; von Loewenich, Friederike D; Rebets, Yuriy; Tokovenko, Bogdan; Luzhetskyy, Andriy N; Merfort, Irmgard; Helmholtz Institute for Pharmaceutical Research Saarland,Saarbrücken, Saarland 66123, Germany. (2015-08)
      Arnica montana L. is a medical plant of the Asteraceae family and grows preferably on nutrient poor soils in mountainous environments. Such surroundings are known to make plants dependent on symbiosis with other organisms. Up to now only arbuscular mycorrhizal fungi were found to act as endophytic symbiosis partners for A. montana. Here we identified five Streptomyces strains, microorganisms also known to occur as endophytes in plants and to produce a huge variety of active secondary metabolites, as inhabitants of A. montana. The secondary metabolite spectrum of these strains does not contain sesquiterpene lactones, but consists of the glutarimide antibiotics cycloheximide and actiphenol as well as the diketopiperazines cyclo-prolyl-valyl, cyclo-prolyl-isoleucyl, cyclo-prolyl-leucyl and cyclo-prolyl-phenylalanyl. Notably, genome analysis of one strain was performed and indicated a huge genome size with a high number of natural products gene clusters among which genes for cycloheximide production were detected. Only weak activity against the Gram-positive bacterium Staphylococcus aureus was revealed, but the extracts showed a marked cytotoxic activity as well as an antifungal activity against Candida parapsilosis and Fusarium verticillioides. Altogether, our results provide evidence that A. montana and its endophytic Streptomyces benefit from each other by completing their protection against competitors and pathogens and by exchanging plant growth promoting signals with nutrients.
    • A gene cluster for the biosynthesis of moenomycin family antibiotics in the genome of teicoplanin producer Actinoplanes teichomyceticus.

      Horbal, Liliya; Ostash, Bohdan; Luzhetskyy, Andriy N; Walker, Suzanne; Kalinowski, Jorn; Fedorenko, Victor; Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland Universitätscampus E8.1, 66123 Saarbrücken, Germany. (2016-09)
      Moenomycins are phosphoglycolipid antibiotics notable for their extreme potency, unique mode of action, and proven record of use in animal nutrition without selection for resistant microflora. There is a keen interest in manipulation of structures of moenomycins in order to better understand their structure-activity relationships and to generate improved analogs. Only two almost identical moenomycin biosynthetic gene clusters are known, limiting our knowledge of the evolution of moenomycin pathways and our ability to genetically diversify them. Here, we report a novel gene cluster (tchm) that directs production of the phosphoglycolipid teichomycin in Actinoplanes teichomyceticus. Its overall genetic architecture is significantly different from that of the moenomycin biosynthesis (moe) gene clusters of Streptomyces ghanaensis and Streptomyces clavuligerus, featuring multiple gene rearrangements and two novel structural genes. Involvement of the tchm cluster in teichomycin biosynthesis was confirmed via heterologous co-expression of amidotransferase tchmH5 and moe genes. Our work sets the background for further engineering of moenomycins and for deeper inquiries into the evolution of this fascinating biosynthetic pathway.
    • Genome Engineering Approaches to Improve Nosokomycin A Production by Streptomyces ghanaensis B38.3

      Kuzhyk, Yuriy; Lopatniuk, Maria; Luzhetskyy, Andriy N; Fedorenko, Victor; Ostash, Bohdan; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Springer, 2018-09-25)
      Here we describe our efforts to improve the levels of phosphoglycolipid antibiotic nosokomycin A production by Streptomyces ghanaensis ATCC14672 via genome engineering approaches. Introduction of two extra copies of leucyl tRNA (UUA) gene bldA and one copy of moenomycin biosynthesis gene cluster led, on average, to threefold increase in nosokomycin A titers (up to 1.5 mg/L). Our results validate genome engineering approach as a viable strategy to improve moenomycin production.
    • Heterologous Expression of the Nybomycin Gene Cluster from the Marine StrainStreptomyces albus subsp. NRRL B-24108.

      Rodríguez Estévez, Marta; Myronovskyi, Maksym; Gummerlich, Nils; Nadmid, Suvd; Luzhetskyy, Andriy N; HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany. (MPDI, 2018-11-04)
      Streptomycetes represent an important reservoir of active secondary metabolites with potential applications in the pharmaceutical industry. The gene clusters responsible for their production are often cryptic under laboratory growth conditions. Characterization of these clusters is therefore essential for the discovery of new microbial pharmaceutical drugs. Here, we report the identification of the previously uncharacterized nybomycin gene cluster from the marine actinomycete
    • Identification of butenolide regulatory system controlling secondary metabolism in Streptomyces albus J1074.

      Ahmed, Yousra; Rebets, Yuriy; Tokovenko, Bogdan; Brötz, Elke; Luzhetskyy, Andriy N; Helmholtz-Institut für pharmazeutische Forschung Saarland,Universitätscampus E8.1, 66123 Saarbrücken, Germany. (2017-08-29)
      A large majority of genome-encrypted chemical diversity in actinobacteria remains to be discovered, which is related to the low level of secondary metabolism genes expression. Here, we report the application of a reporter-guided screening strategy to activate cryptic polycyclic tetramate macrolactam gene clusters in Streptomyces albus J1074. The analysis of the S. albus transcriptome revealed an overall low level of secondary metabolism genes transcription. Combined with transposon mutagenesis, reporter-guided screening resulted in the selection of two S. albus strains with altered secondary metabolites production. Transposon insertion in the most prominent strain, S. albus ATGSal2P2::TN14, was mapped to the XNR_3174 gene encoding an unclassified transcriptional regulator. The mutant strain was found to produce the avenolide-like compound butenolide 4. The deletion of the gene encoding a putative acyl-CoA oxidase, an orthologue of the Streptomyces avermitilis avenolide biosynthesis enzyme, in the S. albus XNR_3174 mutant caused silencing of secondary metabolism. The homologues of XNR_3174 and the butenolide biosynthesis genes were found in the genomes of multiple Streptomyces species. This result leads us to believe that the discovered regulatory elements comprise a new condition-dependent system that controls secondary metabolism in actinobacteria and can be manipulated to activate cryptic biosynthetic pathways.
    • Insights into naturally minimised Streptomyces albus J1074 genome

      Zaburannyi, Nestor; Rabyk, Mariia; Ostash, Bohdan; Fedorenko, Victor; Luzhetskyy, Andriy N (2014-02-05)
      Abstract Background The Streptomyces albus J1074 strain is one of the most widely used chassis for the heterologous production of bioactive natural products. The fast growth and an efficient genetic system make this strain an attractive model for expressing cryptic biosynthetic pathways to aid drug discovery. Results To improve its capabilities for the heterologous expression of biosynthetic gene clusters, the complete genomic sequence of S. albus J1074 was obtained. With a size of 6,841,649 bp, coding for 5,832 genes, its genome is the smallest within the genus streptomycetes. Genome analysis revealed a strong tendency to reduce the number of genetic duplicates. The whole transcriptomes were sequenced at different time points to identify the early metabolic switch from the exponential to the stationary phase in S. albus J1074. Conclusions S. albus J1074 carries the smallest genome among the completely sequenced species of the genus Streptomyces. The detailed genome and transcriptome analysis discloses its capability to serve as a premium host for the heterologous production of natural products. Moreover, the genome revealed 22 additional putative secondary metabolite gene clusters that reinforce the strain’s potential for natural product synthesis.
    • Monitoring Protein Secretion in Using Fluorescent Proteins.

      Hamed, Mohamed Belal; Vrancken, Kristof; Bilyk, Bohdan; Koepff, Joachim; Novakova, Renata; van Mellaert, Lieve; Oldiges, Marco; Luzhetskyy, Andriy N; Kormanec, Jan; Anné, Jozef; et al. (2018-12-07)
      Fluorescent proteins are a major cell biology tool to analyze protein sub-cellular topology. Here we have applied this technology to study protein secretion in the Gram-positive bacterium Streptomyces lividans TK24, a widely used host for heterologous protein secretion biotechnology. Green and monomeric red fluorescent proteins were fused behind Sec (SPSec) or Tat (SPTat) signal peptides to direct them through the respective export pathway. Significant secretion of fluorescent eGFP and mRFP was observed exclusively through the Tat and Sec pathways, respectively. Plasmid over-expression was compared to a chromosomally integrated spSec-mRFP gene to allow monitoring secretion under high and low level synthesis in various media. Fluorimetric detection of SPSec-mRFP recorded folded states, while immuno-staining detected even non-folded topological intermediates. Secretion of SPSec-mRFP is unexpectedly complex, is regulated independently of cell growth phase and is influenced by the growth regime. At low level synthesis, highly efficient secretion occurs until it is turned off and secretory preforms accumulate. At high level synthesis, the secretory pathway overflows and proteins are driven to folding and subsequent degradation. High-level synthesis of heterologous secretory proteins, whether secretion competent or not, has a drastic effect on the endogenous secretome, depending on their secretion efficiency. These findings lay the foundations of dissecting how protein targeting and secretion are regulated by the interplay between the metabolome, secretion factors and stress responses in the S. lividans model.
    • Multi-Omics and Targeted Approaches to Determine the Role of Cellular Proteases in Protein Secretion.

      Busche, Tobias; Tsolis, Konstantinos C; Koepff, Joachim; Rebets, Yuriy; Rückert, Christian; Hamed, Mohamed B; Bleidt, Arne; Wiechert, Wolfgang; Lopatniuk, Mariia; Yousra, Ahmed; et al. (2018-01-01)
    • New Alpiniamides From sp. IB2014/011-12 Assembled by an Unusual Hybrid Non-ribosomal Peptide Synthetase -AT Polyketide Synthase Enzyme.

      Paulus, Constanze; Rebets, Yuriy; Zapp, Josef; Rückert, Christian; Kalinowski, Jörn; Luzhetskyy, Andriy N; HIPS, Helmholtz-Institut füt Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (2018-01-01)
      he environment of Lake Baikal is a well-known source of microbial diversity. The strain Streptomyces sp. IB2014/011-12, isolated from samples collected at Lake Baikal, was found to exhibit potent activity against Gram-positive bacteria. Here, we report isolation and characterization of linear polyketide alpiniamide A (1) and its new derivatives B–D (2–5). The structures of alpiniamides A–D were established and their relative configuration was determined by combination of partial Murata’s method and ROESY experiment. The absolute configuration of alpiniamide A was established through Mosher’s method. The gene cluster, responsible for the biosynthesis of alpiniamides (alp) has been identified by genome mining and gene deletion experiments. The successful expression of the cloned alp gene cluster in a heterologous host supports these findings. Analysis of the architecture of the alp gene cluster and the feeding of labeled precursors elucidated the alpiniamide biosynthetic pathway. The biosynthesis of alpiniamides is an example of a rather simple polyketide assembly line generating unusual chemical diversity through the combination of domain/module skipping and double bond migration events.
    • New natural products identified by combined genomics-metabolomics profiling of marine Streptomyces sp. MP131-18.

      Paulus, Constanze; Rebets, Yuriy; Tokovenko, Bogdan; Nadmid, Suvd; Terekhova, Larisa P; Myronovskyi, Maksym; Zotchev, Sergey B; Rückert, Christian; Braig, Simone; Zahler, Stefan; et al. (2017-02-10)
      Marine actinobacteria are drawing more and more attention as a promising source of new natural products. Here we report isolation, genome sequencing and metabolic profiling of new strain Streptomyces sp. MP131-18 isolated from marine sediment sample collected in the Trondheim Fjord, Norway. The 16S rRNA and multilocus phylogenetic analysis showed that MP131-18 belongs to the genus Streptomyces. The genome of MP131-18 isolate was sequenced, and 36 gene clusters involved in the biosynthesis of 18 different types of secondary metabolites were predicted using antiSMASH analysis. The combined genomics-metabolics profiling of the strain led to the identification of several new biologically active compounds. As a result, the family of bisindole pyrroles spiroindimicins was extended with two new members, spiroindimicins E and F. Furthermore, prediction of the biosynthetic pathway for unusual α-pyrone lagunapyrone isolated from MP131-18 resulted in foresight and identification of two new compounds of this family - lagunapyrones D and E. The diversity of identified and predicted compounds from Streptomyces sp. MP131-18 demonstrates that marine-derived actinomycetes are not only a promising source of new natural products, but also represent a valuable pool of genes for combinatorial biosynthesis of secondary metabolites.