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Tuttle, RN, Demko AM, Patin NV, Kapono CA, Donia MS, Dorrestein P, Jensen PR.  2019.  Detection of natural products and their producers in ocean sediments. Applied and Environmental Microbiology. 85   10.1128/aem.02830-18   AbstractWebsite

Thousands of natural products have been identified from cultured microorganisms, yet evidence of their production in the environment has proven elusive. Technological advances in mass spectrometry, combined with public data-bases, now make it possible to address this disparity by detecting compounds directly from environmental samples. Here, we used adsorbent resins, tandem mass spectrometry, and next-generation sequencing to assess the metabolome of marine sediments and its relationship to bacterial community structure. We identified natural products previously reported from cultured bacteria, providing evidence they are produced in situ, and compounds of anthropogenic origin, suggesting this approach can be used as an indicator of environmental impact. The bacterial metabolite staurosporine was quantified and shown to reach physiologically relevant concentrations, indicating that it may influence sediment community structure. Staurosporine concentrations were correlated with the relative abundance of the staurosporine-producing bacterial genus Salinispora and production confirmed in strains cultured from the same location, providing a link between compound and candidate producer. Metagenomic analyses revealed numerous biosynthetic gene clusters related to indolocarbazole biosynthesis, providing evidence for noncanonical sources of staurosporine and a path forward to assess the relationships between natural products and the organisms that produce them. Untargeted environmental metabolomics circumvents the need for laboratory cultivation and represents a promising approach to understanding the functional roles of natural products in shaping microbial community structure in marine sediments. IMPORTANCE Natural products are readily isolated from cultured bacteria and exploited for useful purposes, including drug discovery. However, these compounds are rarely detected in the environments from which the bacteria are obtained, thus limiting our understanding of their ecological significance. Here, we used environmental metabolomics to directly assess chemical diversity in marine sediments. We identified numerous metabolites and, in one case, isolated strains of bacteria capable of producing one of the compounds detected. Coupling environmental metabolomics with community and metagenomic analyses provides opportunities to link compounds and producers and begin to assess the complex interactions mediated by specialized metabolites in marine sediments.

Gallagher, KA, Wanger G, Henderson J, Llorente M, Hughes CC, Jensen PR.  2017.  Ecological implications of hypoxia-triggered shifts in secondary metabolism. Environmental Microbiology. 19:2182-2191.   10.1111/1462-2920.13700   AbstractWebsite

Members of the actinomycete genus Streptomyces are non-motile, filamentous bacteria that are well-known for the production of biomedically relevant secondary metabolites. While considered obligate aerobes, little is known about how these bacteria respond to periods of reduced oxygen availability in their natural habitats, which include soils and ocean sediments. Here, we provide evidence that the marine streptomycete strain CNQ-525 can reduce MnO2 via a diffusible mechanism. We investigated the effects of hypoxia on secondary metabolite production and observed a shift away from the antibiotic napyradiomycin towards 8-aminoflaviolin, an intermediate in the napyradiomycin biosynthetic pathway. We purified 8-amino-flaviolin and demonstrated that it is reversibly redox-active (midpoint potential -474.5 mV), indicating that it has the potential to function as an endogenous extracellular electron shuttle. This study provides evidence that environmentally triggered changes in secondary metabolite production may provide clues to the ecological functions of specific compounds, and that Gram-positive bacteria considered to be obligate aerobes may play previously unrecognized roles in biogeochemical cycling through mechanisms that include extracellular electron shuttling.

Ziemert, N, Lechner A, Wietz M, Millan-Aguinaga N, Chavarria KL, Jensen PR.  2014.  Diversity and evolution of secondary metabolism in the marine actinomycete genus Salinispora. Proceedings of the National Academy of Sciences of the United States of America. 111:E1130-E1139.   10.1073/pnas.1324161111   AbstractWebsite

Access to genome sequence data has challenged traditional natural product discovery paradigms by revealing that the products of most bacterial biosynthetic pathways have yet to be discovered. Despite the insight afforded by this technology, little is known about the diversity and distributions of natural product biosynthetic pathways among bacteria and how they evolve to generate structural diversity. Here we analyze genome sequence data derived from 75 strains of the marine actinomycete genus Salinispora for pathways associated with polyketide and nonribosomal peptide biosynthesis, the products of which account for some of today's most important medicines. The results reveal high levels of diversity, with a total of 124 pathways identified and 229 predicted with continued sequencing. Recent horizontal gene transfer accounts for the majority of pathways, which occur in only one or two strains. Acquired pathways are incorporated into genomic islands and are commonly exchanged within and between species. Acquisition and transfer events largely involve complete pathways, which subsequently evolve by gene gain, loss, and duplication followed by divergence. The exchange of similar pathway types at the precise chromosomal locations in different strains suggests that the mechanisms of integration include pathway-level homologous recombination. Despite extensive horizontal gene transfer there is clear evidence of species-level vertical inheritance, supporting the concept that secondary metabolites represent functional traits that help define Salinispora species. The plasticity of the Salinispora secondary metabolome provides an effective mechanism to maximize population-level secondary metabolite diversity while limiting the number of pathways maintained within any individual genome.

Alvarez-Mico, X, Jensen PR, Fenical W, Hughes CC.  2013.  Chlorizidine, a Cytotoxic 5H-Pyrrolo 2,1-a isoindol-5-one-Containing Alkaloid from a Marine Streptomyces sp. Organic Letters. 15:988-991.   10.1021/ol303374e   AbstractWebsite

Cultivation of an obligate marine Streptomyces strain has provided the cytotoxic natural product chlorizidine A. X-ray crystallographic analysis revealed that the metabolite is composed of a chlorinated 2,3-dihydropyrrolizine ring attached to a chlorinated 5H-pyrrolo[2,1-a]isoindol-5-one. The carbon stereocenter in the dihydropyrrolizine is S-configured. Remarkably, the 5H-pyrrolo[2,1-a]isoindol-5-one moiety has no precedence in the field of natural products. The presence of this ring system, which was demonstrated to undergo facile nucleophilic substitution reactions at the activated carbonyl group, is essential to the molecule's cytotoxicity against HCT-116 human colon cancer cells.

Cheng, YB, Jensen PR, Fenical W.  2013.  Cytotoxic and antimicrobial napyradiomycins from two marine-derived streptomyces strains. European Journal of Organic Chemistry. :3751-3757.   10.1002/ejoc.201300349   AbstractWebsite

The cancer-cell-cytotoxicity-guided fractionation of the acetone extracts of two cultured marine-derived Streptomyces strains belonging to the MAR4 group yielded six new napyradiomycins, compounds A-F (1-6), together with three known compounds, napyradiomycins B2-B4 (7-9). Napyradiomycins 1-4 are new members of the napyradiomycin C-type meroterpenoids, which possess a linear monoterpene bridge between C-7 and C-10a. Compound 4 has an additional tetrahydropyran ring fused to the phenol moiety. Compounds 5-9 are related to the napyradiomycin B-type meroterpenoids. The structures of all new compounds were assigned by interpretation of 1D and 2D NMR, MS, and other spectroscopic data. The relative configurations were assigned based upon interpretation of ROESY 2D NMR experiments. The cytotoxicity of 1-9 against the human colon carcinoma cell line HCT-116 and their antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) are presented.

Gallagher, KA, Rauscher K, Ioca LP, Jensen PR.  2013.  Phylogenetic and chemical diversity of a hybrid-isoprenoid producing streptomycete lineage. Applied and Environmental Microbiology. 79:6894-6902.   10.1128/aem.01814-13   AbstractWebsite

Streptomyces species dedicate a large portion of their genomes to secondary metabolite biosynthesis. A diverse and largely marine-derived lineage within this genus has been designated MAR4 and identified as a prolific source of hybrid isoprenoid (HI) secondary metabolites. These terpenoid-containing compounds are common in nature but rarely observed as bacterial secondary metabolites. To assess the phylogenetic diversity of the MAR4 lineage, complementary culture-based and culture-independent techniques were applied to marine sediment samples collected off the Channel Islands, CA. The results, including those from an analysis of publically available sequence data and strains isolated as part of prior studies, placed 40 new strains in the MAR4 clade, of which 32 originated from marine sources. When combined with sequences cloned from environmental DNA, 28 MAR4 operational taxonomic units (0.01% genetic distance) were identified. Of these, 82% consisted exclusively of either cloned sequences or cultured strains, supporting the complementarity of these two approaches. Chemical analyses of diverse MAR4 strains revealed the production of five different HI structure classes. All 21 MAR4 strains tested produced at least one HI class, with most strains producing from two to four classes. The two major clades within the MAR4 lineage displayed distinct patterns in the structural classes and the number and amount of HIs produced, suggesting a relationship between taxonomy and secondary metabolite production. The production of HI secondary metabolites appears to be a phenotypic trait of the MAR4 lineage, which represents an emerging model with which to study the ecology and evolution of HI biosynthesis.

Freel, KC, Edlund A, Jensen PR.  2012.  Microdiversity and evidence for high dispersal rates in the marine actinomycete 'Salinispora pacifica'. Environmental Microbiology. 14:480-493.   10.1111/j.1462-2920.2011.02641.x   AbstractWebsite

In July of 2006 and January of 2008, a total of 671 marine sediment samples were collected at depths from 5 to 2012 m throughout the Fijian islands and selectively processed for the cultivation of marine actinomycetes belonging to the genus Salinispora. The primary objectives were to assess the diversity, distribution and phylogeny of 'S. pacifica', the least well studied of the three species in the genus. Employing a sequential screening method based on antibiotic sensitivity, RFLP patterns, and 16S rRNA and ITS sequence analyses, 42 of 750 isolates with Salinispora-like features were identified as 'S. pacifica'. These strains represent the first report of 'S. pacifica' from Fiji and include 15 representatives of 4 new 'S. pacifica' 16S rRNA sequence types. Among the 'S. pacifica' strains isolated, little evidence for geographical isolation emerged based on 16S, ITS or secondary metabolite biosynthetic gene fingerprinting. The inclusion of isolates from additional collection sites and other Salinispora spp. revealed a high degree of dispersal among 'S. pacifica' populations and phylogenetic support for the delineation of this lineage as a third species.

Gonzalez, DJ, Xu YQ, Yang YL, Esquenazi E, Liu WT, Edlund A, Duong T, Du LC, Molnar I, Gerwick WH, Jensen PR, Fischbach M, Liaw CC, Straight P, Nizet V, Dorrestein PC.  2012.  Observing the invisible through imaging mass spectrometry, a window into the metabolic exchange patterns of microbes. Journal of Proteomics. 75:5069-5076.   10.1016/j.jprot.2012.05.036   AbstractWebsite

Many microbes can be cultured as single-species communities. Often, these colonies are controlled and maintained via the secretion of metabolites. Such metabolites have been an invaluable resource for the discovery of therapeutics (e.g. penicillin, taxol, rapamycin, epothilone). In this article, written for a special issue on imaging mass spectrometry, we show that MALDI-imaging mass spectrometry can be adapted to observe, in a spatial manner, the metabolic exchange patterns of a diverse array of microbes, including thermophilic and mesophilic fungi, cyanobacteria, marine and terrestrial actinobacteria, and pathogenic bacteria. Dependent on media conditions, on average and based on manual analysis, we observed 11.3 molecules associated with each microbial IMS experiment, which was split nearly 50:50 between secreted and colony-associated molecules. The spatial distributions of these metabolic exchange factors are related to the biological and ecological functions of the organisms. This work establishes that MALDI-based IMS can be used as a general tool to study a diverse array of microbes. Furthermore the article forwards the notion of the IMS platform as a window to discover previously unreported molecules by monitoring the metabolic exchange patterns of organisms when grown on agar substrates. This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User's Guide to a New Technique for Biological and Biomedical Research. Published by Elsevier B.V.

Freel, KC, Nam SJ, Fenical W, Jensen PR.  2011.  Evolution of Secondary Metabolite Genes in Three Closely Related Marine Actinomycete Species. Applied and Environmental Microbiology. 77:7261-7270.   10.1128/aem.05943-11   AbstractWebsite

The marine actinomycete genus Salinispora is composed of three closely related species. These bacteria are a rich source of secondary metabolites, which are produced in species-specific patterns. This study examines the distribution and phylogenetic relationships of genes involved in the biosynthesis of secondary metabolites in the salinosporamide and staurosporine classes, which have been reported for S. tropica and S. arenicola, respectively. The focus is on "Salinispora pacifica," the most recently discovered and phylogenetically diverse member of the genus. Of 61 S. pacifica strains examined, 15 tested positive for a ketosynthase (KS) domain linked to the biosynthesis of salinosporamide K, a new compound in the salinosporamide series. Compound production was confirmed in two strains, and the domain phylogeny supports vertical inheritance from a common ancestor shared with S. tropica, which produces related compounds in the salinosporamide series. There was no evidence for interspecies recombination among salA KS sequences, providing further support for the geographic isolation of these two salinosporamide-producing lineages. In addition, staurosporine production is reported for the first time for S. pacifica, with 24 of 61 strains testing positive for staD, a key gene involved in the biosynthesis of this compound. High levels of recombination were observed between staD alleles in S. pacifica and the cooccurring yet more distantly related S. arenicola, which produces a similar series of staurosporines. The distributions and phylogenies of the biosynthetic genes examined provide insight into the complex processes driving the evolution of secondary metabolism among closely related bacterial species.

Haste, NM, Hughes CC, Tran DN, Fenical W, Jensen PR, Nizet V, Hensler ME.  2011.  Pharmacological Properties of the Marine Natural Product Marinopyrrole A against Methicillin-Resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy. 55:3305-3312.   10.1128/aac.01211-10   AbstractWebsite

The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains in hospital and community settings presents a great challenge to public health and illustrates the urgency of discovering new antibiotics. Marinopyrrole A is a member of a structurally novel class of compounds identified from a species of marine-derived streptomycetes with evidence of antistaphylococcal activity. We show that marinopyrrole A has potent concentration-dependent bactericidal activity against clinically relevant hospital-and community-acquired MRSA strains, a prolonged postantibiotic effect superior to that of the current first-line agents vancomycin and linezolid, and a favorable resistance profile. Marinopyrrole A showed limited toxicity to mammalian cell lines (at >20x MIC). However, its antibiotic activity against MRSA was effectively neutralized by 20% human serum. A variety of marinopyrrole analogs were isolated from culture or synthetically produced to try to overcome the inhibitory effect of serum. While many of these compounds retained potent bactericidal effect against MRSA, their activities were also inhibited by serum. Marinopyrrole A has significant affinity for plastic and may therefore have potential as a potent anti-MRSA agent in cutaneous, intracatheter, or antibiotic-lock applications.

Jensen, PR.  2010.  Linking species concepts to natural product discovery in the post-genomic era. Journal of Industrial Microbiology & Biotechnology. 37:219-224.   10.1007/s10295-009-0683-z   AbstractWebsite

A widely accepted species concept for bacteria has yet to be established. As a result, species designations are inconsistently applied and tied to what can be considered arbitrary metrics. Increasing access to DNA sequence data and clear evidence that bacterial genomes are dynamic entities that include large numbers of horizontally acquired genes have added a new level of insight to the ongoing species concept debate. Despite uncertainties over how to apply species concepts to bacteria, there is clear evidence that sequence-based approaches can be used to resolve cohesive groups that maintain the properties of species. This cohesion is clearly evidenced in the genus Salinispora, where three species have been discerned despite very close relationships based on 16S rRNA sequence analysis. The major phenotypic differences among the three species are associated with secondary metabolite production, which occurs in species-specific patterns. These patterns are maintained on a global basis and provide evidence that secondary metabolites have important ecological functions. These patterns also suggest that an effective strategy for natural product discovery is to target the cultivation of new Salinispora taxa. Alternatively, bioinformatic analyses of biosynthetic genes provide opportunities to predict secondary metabolite novelty and reduce the redundant isolation of well-known metabolites. Although much remains to be learned about the evolutionary relationships among bacteria and how fundamental units of diversity can be resolved, genus and species descriptions remain the most effective method of scientific communication.

Murphy, BT, Narender T, Kauffman CA, Woolery M, Jensen PR, Fenical W.  2010.  Saliniquinones A-F, New Members of the Highly Cytotoxic Anthraquinone-gamma-Pyrones from the Marine Actinomycete Salinispora arenicola. Australian Journal of Chemistry. 63:929-934.   10.1071/ch10068   AbstractWebsite

Six newanthraquinone-gamma-pyrones, saliniquinones A-F (1-6), which are related to metabolites of the pluramycin/altromycin class, were isolated from a fermentation broth of the marine actinomycete Salinispora arenicola (strain CNS-325). Their structures were determined by analysis of one-and two-dimensional NMR spectroscopic and high-resolution mass spectrometric data. The relative and absolute configurations of compounds 1-6 were determined by analysis of NOESY NMR spectroscopic data and by comparison of circular dichroism and optical rotation data with model compounds found in the literature. Saliniquinone A (1) exhibited potent inhibition of the human colon adenocarcinoma cell line (HCT-116) with an IC(50) of 9.9 x 10(-9) M. In the context of the biosynthetic diversity of S. arenicola, compounds 1-6 represent secondary metabolites that appear to be strain specific and thus occur outside of the core group of compounds commonly observed from this species.

Penn, K, Jenkins C, Nett M, Udwary DW, Gontang EA, McGlinchey RP, Foster B, Lapidus A, Podell S, Allen EE, Moore BS, Jensen PR.  2009.  Genomic islands link secondary metabolism to functional adaptation in marine Actinobacteria. Isme Journal. 3:1193-1203.   10.1038/ismej.2009.58   AbstractWebsite

Genomic islands have been shown to harbor functional traits that differentiate ecologically distinct populations of environmental bacteria. A comparative analysis of the complete genome sequences of the marine Actinobacteria Salinispora tropica and Salinispora arenicola reveals that 75% of the species-specific genes are located in 21 genomic islands. These islands are enriched in genes associated with secondary metabolite biosynthesis providing evidence that secondary metabolism is linked to functional adaptation. Secondary metabolism accounts for 8.8% and 10.9% of the genes in the S. tropica and S. arenicola genomes, respectively, and represents the major functional category of annotated genes that differentiates the two species. Genomic islands harbor all 25 of the species-specific biosynthetic pathways, the majority of which occur in S. arenicola and may contribute to the cosmopolitan distribution of this species. Genome evolution is dominated by gene duplication and acquisition, which in the case of secondary metabolism provide immediate opportunities for the production of new bioactive products. Evidence that secondary metabolic pathways are exchanged horizontally, coupled with earlier evidence for fixation among globally distributed populations, supports a functional role and suggests that the acquisition of natural product biosynthetic gene clusters represents a previously unrecognized force driving bacterial diversification. Species-specific differences observed in clustered regularly interspaced short palindromic repeat sequences suggest that S. arenicola may possess a higher level of phage immunity, whereas a highly duplicated family of polymorphic membrane proteins provides evidence for a new mechanism of marine adaptation in Gram-positive bacteria. The ISME Journal (2009) 3, 1193-1203; doi:10.1038/ismej.2009.58; published online 28 May 2009

Kwon, HC, Kauffman CA, Jensen PR, Fenical W.  2009.  Marinisporolides, Polyene-Polyol Macrolides from a Marine Actinomycete of the New Genus Marinispora. Journal of Organic Chemistry. 74:675-684.   10.1021/jo801944d   AbstractWebsite

Two new polyene macrolides, marinisporolides A and B (1, 2), were isolated from the saline culture of the marine actinomycete, strain CNQ-140, identified as a member of the new marine genus Marinispora. The marinisporolides are 34-membered macrolides composed of a conjugated pentaene and several pairs of 1,3-dihydroxyl functionalities. Marinisporolide A (1) contains a bicyclic spiro-bis-tetrahydropyran ketal functionality, while marinisporolide B (2) is the corresponding hemiketal. The structures of these new compounds were assigned by combined spectral and chemical methods including extensive 2D NMR experiments and correlations of (13)C NMR data with Kishi's Universal NMR Database. Chemical modifications, including methanolysis, acetonide formation, and application of the modified Mosher method, provided the full stereostructures of these molecules. Three additional macrolides, marinisporolides C-E (3-5), which are olefin geometric isomers of marinisporolide A (1), were also isolated and their structures defined. Under room light, marinisporolides A and B readily photoisomerize to C-E indicating that they are most likely produced by photochemical conversion during the cultivation or isolation procedures. Although polyenes, marinisporolides A (1) and B (2) showed weak to no antifungal activity against Candida albicans.

Udwary, DW, Zeigler L, Asolkar RN, Singan V, Lapidus A, Fenical W, Jensen PR, Moore BS.  2007.  Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proceedings of the National Academy of Sciences of the United States of America. 104:10376-10381.   10.1073/pnas.0700962104   AbstractWebsite

Recent fermentation studies have identified actinomycetes of the marine-dwelling genus Salinispora as prolific natural product producers. To further evaluate their biosynthetic potential, we sequenced the 5,183,331-bp S. tropica CNB-440 circular genome and analyzed all identifiable secondary natural product gene clusters. Our analysis shows that S. tropica dedicates a large percentage of its genome (approximate to 9.9%) to natural product assembly, which is greater than previous Streptomyces genome sequences as well as other natural product-producing actinomycetes. The S. tropica genome features polyketide synthase systems of every known formally classified family, nonribosomal peptide synthetases, and several hybrid clusters. Although a few clusters appear to encode molecules previously identified in Streptomyces species, the majority of the 17 biosynthetic loci are novel. Specific chemical information about putative and observed natural product molecules is presented and discussed. In addition, our bioinformatic analysis not only was critical for the structure elucidation of the polyene macrolactam salinilactam A, but its structural analysis aided the genome assembly of the highly repetitive slm loci. This study firmly establishes the genus Salinispora as a rich source of drug-like molecules and importantly reveals the powerful interplay between genomic analysis and traditional natural product isolation studies.

Williams, PG, Miller ED, Asolkar RN, Jensen PR, Fenical W.  2007.  Arenicolides A-C, 26-membered ring macrolides from the marine actinomycete Salinispora arenicola. Journal of Organic Chemistry. 72:5025-5034.   10.1021/jo061878x   AbstractWebsite

Chemical evaluation of the saline fermentation broth of several strains of the obligate marine actinomycete Salinispora arenicola has led to the identification of three new macrolide polyketides designated arenicolides A-C (1-3). The planar structures, elucidated via spectroscopic and chemical methods, consist of 26-membered polyunsaturated macrolactones containing repeating vicinal hydroxyl methoxyl moieties. The relative and absolute stereochemistries of 1-3 were assigned by a combination of J-based configurational analyses and chemical derivatization.

Miller, ED, Kauffman CA, Jensen PR, Fenical W.  2007.  Piperazimycins: Cytotoxic hexadepsipeptides from a marine-derived bacterium of the genus Streptomyces. Journal of Organic Chemistry. 72:323-330.   10.1021/jo061064g   AbstractWebsite

[graphics] Three potent cancer cell cytotoxins, piperazimycins A-C (1-3), have been isolated from the fermentation broth of a Streptomyces sp., cultivated from marine sediments near the island of Guam. The structures of these cyclic hexadepsipeptides were assigned by a combination of spectral, chemical, and crystallographic methods. The piperazimycins are composed of rare amino acids, including hydroxyacetic acid, alpha-methylserine, gamma-hydroxypiperazic acid, and gamma-chloropiperazic acid. The novel amino acid residues 2-amino-8-methyl-4,6-nonadienoic acid and 2-amino-8-methyl-4,6-decadienoic acid were found as components of piperazimycins A and C, respectively. When screened in the National Cancer Institute's 60 cancer cell line panel, piperazimycin A exhibited potent in vitro cytotoxicity toward multiple tumor cell lines with a mean GI(50) of 100 nM.

Jensen, PR, Williams PG, Oh DC, Zeigler L, Fenical W.  2007.  Species-specific secondary metabolite production in marine actinomycetes of the genus Salinispora. Applied and Environmental Microbiology. 73:1146-1152.   10.1128/aem.01891-06   AbstractWebsite

Here we report associations between secondary metabolite production and phylogenetically distinct but closely related marine actinomycete species belonging to the genus Salinispora. The pattern emerged in a study that included global collection sites, and it indicates that secondary metabolite production can be a species-specific, phenotypic trait associated with broadly distributed bacterial populations. Associations between actinomycete phylotype and chemotype revealed an effective, diversity-based approach to natural product discovery that contradicts the conventional wisdom that secondary metabolite production is strain specific. The structural diversity of the metabolites observed, coupled with gene probing and phylogenetic analyses, implicates lateral gene transfer as a source of the biosynthetic genes responsible for compound production. These results conform to a model of selection-driven pathway fixation occurring subsequent to gene acquisition and provide a rare example in which demonstrable physiological traits have been correlated to the fine-scale phylogenetic architecture of an environmental bacterial community.

Cho, JY, Kwon HC, Williams PG, Jensen PR, Fenical W.  2006.  Azamerone, a terpenoid phthalazinone from a marine-derived bacterium related to the genus Streptomyces (actinomycetales). Organic Letters. 8:2471-2474.   10.1021/ol060630r   AbstractWebsite

A novel meroterpenoid, azamerone, was isolated from the saline culture of a new marine-derived bacterium related to the genus Streptomyces. Azamerone is composed of an unprecedented chloropyranophthalazinone core with a 3-chloro-6-hydroxy-2,2,6-trimethylcyclohexylmethyl side chain. The structure was rigorously determined by NMR spectroscopy and X-ray crystallography. A possible biosynthetic origin of this unusual ring system is proposed.

Jensen, PR, Mincer TJ, Williams PG, Fenical W.  2005.  Marine actinomycete diversity and natural product discovery. Antonie Van Leeuwenhoek International Journal of General and Molecular Microbiology. 87:43-48.   10.1007/s10482-004-6540-1   AbstractWebsite

Microbial natural products remain an important resource for drug discovery yet the microorganisms inhabiting the world's oceans have largely been overlooked in this regard. The recent discovery of novel secondary metabolites from taxonomically unique populations of marine actinomycetes suggests that these bacteria add an important new dimension to microbial natural product research. Continued efforts to characterize marine actinomycete diversity and how adaptations to the marine environment affect secondary metabolite production will create a better understanding of the potential utility of these bacteria as a source of useful products for biotechnology.

Hardt, IH, Jensen PR, Fenical W.  2000.  Neomarinone, and new cytotoxic marinone derivatives, produced by a marine filamentous bacterium (actinomycetales). Tetrahedron Letters. 41:2073-2076.   10.1016/s0040-4039(00)00117-9   AbstractWebsite

Neomarinone (1), a novel metabolite possessing a new sesquiterpene- and polyketide-derived carbon skeleton, and several derivatives, 3-5, of the marinone class of naphthoquinone antibiotics, were isolated from the fermentation broth of a taxonomically-novel marine actinomycete (strain #CNH-099). The structures of the new compounds were determined by comprehensive NMR and mass spectral analyses. Neomarinone (1) and several of the marinone derivatives were shown to be moderately cytotoxic toward human cancer cells in in vitro testing. (C) 2000 Elsevier Science Ltd. All rights reserved.

Trischman, JA, Jensen PR, Fenical W.  1994.  Halobacillin - a Cytotoxic Cyclic Acylpeptide of the Iturin Class Produced by a Marine Bacillus. Tetrahedron Letters. 35:5571-5574.   10.1016/s0040-4039(00)77249-2   AbstractWebsite

Halobacillin (1), a new cyclic acylpeptide of the iturin class, has been isolated from cultures of a Bacillus species (culture # CND-914) obtained from a deep-sea sediment core. The structure of the new compound was assigned on the basis of comprehensive NMR studies of 1 and methyl halobacillin (2), and evaluation of the amino acids obtained by acid hydrolysis.