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Farnaes, L, Coufal NG, Kauffman CA, Rheingold AL, DiPasquale AG, Jensen PR, Fenical W.  2014.  Napyradiomycin derivatives, produced by a marine-derived actinomycete, illustrate cytotoxicity by induction of apoptosis. Journal of Natural Products. 77:15-21.   10.1021/np400466j   AbstractWebsite

The microbial production, isolation, and structure elucidation of four new napyradiomycin congeners (1-4) is reported. The structures of these compounds, which are new additions to the marine-derived meroterpenoids, were defined by comprehensive spectroscopic analysis and by X-ray crystallography. Using fluorescence-activated cell sorting (FACS) analysis, napyradiomycins 1-4 were observed to induce apoptosis in the colon adenocarcinoma cell line HCT-116, indicating the possibility of a specific biochemical target for this 1 class of cytotoxins.

Feling, RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W.  2003.  Salinosporamide A: A highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus Salinospora. Angewandte Chemie-International Edition. 42:355-+.   10.1002/anie.200390115   Website
Fenical, W, Jensen PR.  2006.  Developing a new resource for drug discovery: marine actinomycete bacteria. Nature Chemical Biology. 2:666-673.   10.1038/nchembio841   AbstractWebsite

Natural products are both a fundamental source of new chemical diversity and an integral component of today's pharmaceutical compendium. Yet interest in natural-product drug discovery has waned, in part owing to diminishing returns from traditional resources such as soil bacteria. The oceans cover 70% of the Earth's surface and harbor most of the planet's biodiversity. Although marine plants and invertebrates have received considerable attention as a resource for natural-product discovery, the microbiological component of this diversity remains relatively unexplored. Recent studies have revealed that select groups of marine actinomycetes are a robust source of new natural products. Members of the genus Salinispora have proven to be a particularly rich source of new chemical structures, including the potent proteasome inhibitor salinosporamide A, and other distinct groups are yielding new classes of terpenoids, amino acid-derived metabolites and polyene macrolides. The continued development of improved cultivation methods and technologies for accessing deep-sea environments promises to provide access to this significant new source of chemical diversity.

Fenical, W, Jensen PR, Palladino MA, Lam KS, Lloyd GK, Potts BC.  2009.  Discovery and development of the anticancer agent salinosporamide A (NPI-0052). Bioorganic & Medicinal Chemistry. 17:2175-2180.   10.1016/j.bmc.2008.10.075   AbstractWebsite

The discovery of the anticancer agent salinosporamide A (NPI-0052) resulted from the exploration of new marine environments and a commitment to the potential of the ocean to yield new natural products for drug discovery and development. Driving the success of this process was the linkage of academic research together with the ability and commitment of industry to undertake drug development and provide the resources and expertise to advance the entry of salinosporamide A (NPI-0052) into human clinical trials. This paper offers a chronicle of the important events that facilitated the rapid clinical development of this exciting molecule. (C) 2008 Elsevier Ltd. All rights reserved.

Fenical, W, Jensen PR, Kauffman C, Mayhead SL, Faulkner DJ, Sincich C, Rao MR, Kantorowski EJ, West LM, Strangman WK, Shimizu Y, Li B, Thammana S, Drainville K, Davies-Coleman MT, Kramer RA, Fairchild CR, Rose WC, Wild RC, Vite GD, Peterson RW.  2003.  New anticancer drugs from cultured and collected marine organisms. Pharmaceutical Biology. 41:6-14.   10.1080/1388020039051741   AbstractWebsite

This paper provides an outline of a collaborative research project between researchers at the University of California, San Diego, University of Rhode Island, and the Bristol-Myers Squibb Pharmaceutical Research Institute, with participating members from the Developmental Therapeutics Branch of the National Cancer Institute. The program, formally funded by the National Cancer Institute under the National Cooperative Drug Discovery Groups (NCDDG) program, seeks to discover new anticancer drugs from marine organisms, in particular invertebrates such as sponges and ascidians, and marine microalgae, marine bacteria and fungi. In this report, the program and results obtained since its beginning in 2000 will be summarized.

Fenical, W, Jensen PR.  1993.  Marine Microorganisms: A New Biomedical Resource. Marine Biotechnology. Volume 1, Pharmaceutical and Bioactive Natural Products. 1( Attaway DH, Zaborsky OR, Eds.).:419-459., New York; London: Plenum Press
Floros, DJ, Jensen PR, Dorrestein PC, Koyama N.  2016.  A metabolomics guided exploration of marine natural product chemical space. Metabolomics. 12   10.1007/s11306-016-1087-5   AbstractWebsite

Introduction Natural products from culture collections have enormous impact in advancing discovery programs for metabolites of biotechnological importance. These discovery efforts rely on the metabolomic characterization of strain collections. Objective Many emerging approaches compare metabolomic profiles of such collections, but few enable the analysis and prioritization of thousands of samples from diverse organisms while delivering chemistry specific read outs. Method In this work we utilize untargeted LC-MS/MS based metabolomics together with molecular networking to inventory the chemistries associated with 1000 marine microorganisms. Result This approach annotated 76 molecular families (a spectral match rate of 28 %), including clinically and biotechnologically important molecules such as valinomycin, actinomycin D, and desferrioxamine E. Targeting a molecular family produced primarily by one microorganism led to the isolation and structure elucidation of two new molecules designated maridric acids A and B. Conclusion Molecular networking guided exploration of large culture collections allows for rapid dereplication of know molecules and can highlight producers of uniques metabolites. These methods, together with large culture collections and growing databases, allow for data driven strain prioritization with a focus on novel chemistries.

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.

Freel, KC, Millan-Aguinaga N, Jensen PR.  2013.  Multilocus sequence typing reveals evidence of homologous recombination linked to antibiotic resistance in the genus salinispora. Applied and Environmental Microbiology. 79:5997-6005.   10.1128/aem.00880-13   AbstractWebsite

The three closely related species that currently comprise the genus Salinispora were analyzed using a multilocus sequence typing approach targeting 48 strains derived from four geographic locations. Phylogenetic congruence and a well-supported concatenated tree provide strong support for the delineation of the three species as currently described and the basal relationship of Salinispora arenicola to the more recently diverged sister taxa S. tropica and S. pacifica. The phylogeny of the initial region of the rpoB gene sequenced was atypical, placing the related genera Micromonospora and Verrucosispora within the Salinispora clade. This phylogenetic incongruence was subsequently ascribed to a homologous-recombination event in a portion of the gene associated with resistance to compounds in the rifamycin class, which target RpoB. All S. arenicola strains produced compounds in this class and possessed resistance-conferring amino acid changes in RpoB. The phylogeny of a region of the rpoB gene that is not associated with rifamycin resistance was congruent with the other housekeeping genes. The link between antibiotic resistance and homologous recombination suggests that incongruent phylogenies provide opportunities to identify the molecular targets of secondary metabolites, an observation with potential relevance for drug discovery efforts. Low ratios of interspecies recombination to mutation, even among cooccurring strains, coupled with high levels of within-species recombination suggest that the three species have been described in accordance with natural barriers to recombination.

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.

Fukuda, T, Miller ED, Clark BR, Alnauman A, Murphy CD, Jensen PR, Fenical W.  2011.  Structures and Biosynthesis of the Pyridinopyrones, Polyenepyrones from a Marine-Derived Streptomyces Species. Journal of Natural Products. 74:1773-1778.   10.1021/np200323e   AbstractWebsite

Three polyenylpyrone metabolites, pyridinopyrones A to C (1-3), have been isolated from the culture broth of a marine-derived Streptomyces sp., strain CNQ-301. The structures of the pyridinopyrones were assigned on the basis of chemical modification and combined spectroscopic methods, focusing on interpretation of 1D and 2D NMR data. Pyridinopyrones B and C (2, 3), examined as an inseparable mixture of methyl positional isomers, were ultimately defined by hydrogenation and NMR analysis of a saturated derivative. The biosynthesis of these metabolites was defined by the incorporation of stable isotope-labeled precursors, revealing that the biosynthetic starter unit is nicotinic acid, while the polyene chain and pendant methyl groups are acetate- and methionine-derived, respectively.