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Kang, H, Jensen PR, Fenical W.  1996.  Isolation of microbial antibiotics from a marine ascidian of the genus Didemnum. Journal of Organic Chemistry. 61:1543-1546.   10.1021/jo951794g   Website
Kaysser, L, Bernhardt P, Nam SJ, Loesgen S, Ruby JG, Skewes-Cox P, Jensen PR, Fenical W, Moore BS.  2012.  Merochlorins A-D, Cyclic Meroterpenoid Antibiotics Biosynthesized in Divergent Pathways with Vanadium-Dependent Chloroperoxidases. Journal of the American Chemical Society. 134:11988-11991.   10.1021/ja305665f   AbstractWebsite

Meroterpenoids are mixed polyketide-terpenoid natural products with a broad range of biological activities. Herein, we present the structures of four new meroterpenoid antibiotics, merochlorins A-D, produced by the marine bacterium Streptomyces sp. strain CNH-189, which possess novel chemical skeletons unrelated to known bacterial agents. Draft genome sequencing, mutagenesis, and heterologous biosynthesis in the genome-minimized model actinomycete Streptomyces coelicolor provided the 57.6 kb merochlorin gene cluster that contains two genes encoding rare bacterial vanadium-dependent haloperoxidase (VHPO) genes. Pathway expression of two different fosmid clones that differ largely by the presence or absence of the VHPO gene mcl40 resulted in the differential biosynthesis of merochlorin C, suggesting that Mcl40 catalyzes an unprecedented 15-membered chloronium-induced macrocyclization reaction converting merochlorin D to merochlorin C.

Kelly, SR, Jensen PR, Henkel TP, Fenical W, Pawlik JR.  2003.  Effects of Caribbean sponge extracts on bacterial attachment. Aquatic Microbial Ecology. 31:175-182.   10.3354/ame031175   AbstractWebsite

Attachment is one of the first steps in bacterial colonization. By inhibiting bacterial attachment on surface cells, sponges may not only prevent infection, but also the process of biofouling. Crude organic extracts from 26 species of Caribbean sponges were assayed for their ability to inhibit bacterial attachment. Bacterial attachment was tested using Vibrio harveyi, a motile marine bacterium, isolated from seawater collected above one of the reefs from which sponges were sampled. Extracts were incorporated into agar blocks at concentrations volumetrically equivalent to whole sponge tissue. Extracts from 21 of 26 species (81%) resulted in bacterial attachment on treated blocks that was <40% of attachment on controls. Of these extracts, 9 were particularly active, with mean levels of attachment <8% of controls (Agelas conifera, Ailochroia crassa, Aka coralliphagum, Amphimedon compressa, Aplysina fulva, Erylus formosus, Plakortis halichondroides, Ptilocaulis spiculifera, Verongula gigantea). Extracts from 4 species (Ailochroia crassa, Chondrilla nucula, Ectyoplasia ferox, and Iotrochota birotulata) inhibited bacterial attachment in this assay but were not found to inhibit bacterial growth in a previous study. Purified compounds that deterred feeding of predatory fishes in a prior study were also tested for their effects on bacterial attachment; they were: oroidin, 4,5-dibromopyrrole-2-carboxylic acid and sceptrin from Agelas species, amphitoxin from A. compressa, aeroplysinin-1 and dibromocyclohexadienone from Aplysina species, steroidal glycosides from E. ferox, and formoside from E. formosus. Of these, all but the steroidal glycosides from E. ferox deterred bacterial attachment at natural concentrations, providing evidence that sponge secondary metabolites may have multiple ecological functions.

Kelly, SR, Garo E, Jensen PR, Fenical W, Pawlik JR.  2005.  Effects of Caribbean sponge secondary metabolites on bacterial surface colonization. Aquatic Microbial Ecology. 40:191-203.   10.3354/ame040191   AbstractWebsite

Crude organic tissue extracts from 8 species of Caribbean sponges were assayed for inhibitory effects on surface colonization using 24 environmental marine bacterial isolates, 4 known marine invertebrate pathogens, and 1 common fouling bacterium. Each extract was tested for its effects on bacterial attachment, growth and swarming. The 24 bacterial strains were isolated from sponge surfaces, nearby substrata, or adjacent seawater. Extracts were incorporated into agar for assays of bacterial attachment and swarming, Growth-inhibition assays were conducted with the standard agar disk-diffusion assay. Of the 24 bacterial isolates, 23 were significantly inhibited from attaching to an extract-treated agar surface; 1 isolate from the surface of Agelas conifera exhibited significantly enhanced attachment on agar treated with the extract of that sponge. Sponge extracts had the least effect on growth: of 184 assays, 11 displayed significant antibacterial activity, all of these from 4 sponge species (A. conifera, Ailochroia crassa, Amphimedon compressa, and Aplysina fulva). The same isolate from the surface of A. conifera that exhibited enhanced attachment in response to the extract of that sponge exhibited inhibited growth in response to the same extract. Six out of 24 bacterial isolates exhibited swarming, the majority (67%) of which were isolated from substratum sources. Extracts from 4 of the 8 sponge species (the same species as listed above) inhibited swarming in all 6 strains, while the remaining extracts enhanced, inhibited, or had no effect on swarming depending on the strain. Bioassay-guided fractionation of the extract of A. crassa yielded 2 compounds responsible for inhibiting attachment and swarming, respectively. Ianthellin was identified as the metabolite that inhibited attachment, whereas another brominated tryosine metabolite inhibited swarming. Chemical defenses of sponges may target microbial attachment, and to a lesser degree influence swarming and growth. Non-toxic metabolites may play the greatest role in affecting bacterial epibiosis on the surfaces of marine sponges.

Kim, MC, Machado H, Jang KH, Trzoss L, Jensen PR, Fenical W.  2018.  Integration of genomic data with NMR analysis enables assignment of the full stereostructure of Neaumycin B, a potent inhibitor of glioblastoma from a marine-derived micromonospora. Journal of the American Chemical Society. 140:10775-10784.   10.1021/jacs.8b04848   AbstractWebsite

The microbial metabolites known as the macrolides are some of the most successful natural products used to treat infectious and immune diseases. Describing the structures of these complex metabolites, however, is often extremely difficult due to the presence of multiple stereogenic centers inherent in this class of polyketide-derived metabolites. With the availability of genome sequence data and a better understanding of the molecular genetics of natural product biosynthesis, it is now possible to use bioinformatic approaches in tandem with spectroscopic tools to assign the full stereostructures of these complex metabolites. In our quest to discover and develop new agents for the treatment of cancer, we observed the production of a highly cytotoxic macrolide, neaumycin B, by a marine-derived actinomycete bacterium of the genus Micromonospora. Neaumycin B is a complex polycyclic macrolide possessing 19 asymmetric centers, usually requiring selective degradation, crystallization, derivatization, X-ray diffraction analysis, synthesis, or other time-consuming approaches to assign the complete stereostructure. As an alternative approach, we sequenced the genome of the producing strain and identified the neaumycin gene cluster (neu). By integrating the known stereospecificities of biosynthetic enzymes with comprehensive NMR analysis, the full stereostructure of neaumycin B was confidently assigned. This approach exemplifies how mining gene cluster information while integrating NMR-based structure data can achieve rapid, efficient, and accurate stereostructural assignments for complex macrolides.

Kubanek, J, Jensen PR, Keifer PA, Sullards MC, Collins DO, Fenical W.  2003.  Seaweed resistance to microbial attack: A targeted chemical defense against marine fungi. Proceedings of the National Academy of Sciences of the United States of America. 100:6916-6921.   10.1073/pnas.1131855100   AbstractWebsite

Pathogenic microbes can devastate populations of marine plants and animals. Yet, many sessile organisms such as seaweeds and sponges suffer remarkably low levels of microbial infection, despite lacking cell-based immune systems. Antimicrobial defenses of marine organisms are largely uncharacterized, although from a small number of studies it appears that chemical defenses may improve host resistance. In this study, we asked whether the common seaweed Lobophora variegata is chemically defended against potentially deleterious microorganisms. Using bioassay-guided fractionation, we isolated and characterized a 22-membered cyclic lactone, lobophorolide (1), of presumed polyketide origin, with sub-muM activity against pathogenic and saprophytic marine fungi. Deterrent concentrations of 1 were found in 46 of 51 samples collected from 10 locations in the Bahamas over a 4-year period. Lobophorolide (1) is structurally unprecedented, yet parts of the molecule are related to tolytoxin, the scytophycins, and the swinholides, macrolicles previously isolated from terrestrial cyanobacteria and from marine sponges and gastropods. Until now, compounds of this structural class have not been associated with marine macrophytes. Our findings suggest that seaweeds use targeted antimicrobial chemical defense strategies and that secondary metabolites important in the ecological interactions between marine macroorganisms and microorganisms could be a promising source of novel bioactive compounds.

Kwon, HC, Espindola A, Park JS, Prieto-Davo A, Rose M, Jensen PR, Fenical W.  2010.  Nitropyrrolins A-E, Cytotoxic Farnesyl-alpha-nitropyrroles from a Marine-Derived Bacterium within the Actinomycete Family Streptomycetaceae. Journal of Natural Products. 73:2047-2052.   10.1021/np1006229   AbstractWebsite

Five new farnesyl-alpha-nitropyrroles, nitropyrrolins A-E (1-5), were isolated from the saline culture of the marine actinomycete strain CNQ-509. This strain belongs to the "MAR4" group of marine actinomycetes, which have been demonstrated to be a rich source of hybrid isoprenoid secondary metabolites. The structures of the nitropyrrolins are composed of alpha-nitropyrroles with functionalized farnesyl groups at the C-4 position. These compounds are the first examples of naturally occurring terpenyl-alpha-nitropyrroles. Chemical modifications, including one-step acetonide formation from an epoxide, and application of the modified Mosher method provided the full stereostructures and absolute configurations of these compounds. Several of the nitropyrrolins, nitropyrrolin D in particular, are cytotoxic toward HCT-116 human colon carcinoma cells, but show weak to little antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).

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.

Kwon, HC, Kauffman CA, Jensen PR, Fenical W.  2006.  Marinomycins A-D, antitumor-antibiotics of a new structure class from a marine actinomycete of the recently discovered genus "Marinispora". Journal of the American Chemical Society. 128:1622-1632.   10.1021/ja0558948   AbstractWebsite

Four antitumor-antibiotics of a new structure class, the marinomycins A-D (1-4), were isolated from the saline culture of a new group of marine actinomycetes, for which we have proposed the name "Marinispora". The structures of the marinomycins, which are unusual macrodiolides composed of dimeric 2-hydroxy-6-alkenyl-benzoic acid lactones with conjugated tetraene-pentahydroxy polyketide chains, were assigned by combined spectral and chemical methods. In room light, marinomycin A slowly isomerizes to its geometrical isomers marinomycins B and C. Marinomycins A-D show significant antimicrobial activities against drug resistant bacterial pathogens and demonstrate impressive and selective cancer cell cytotoxicities against six of the eight melanoma cell lines in the National Cancer Institute's 60 cell line panel. The discovery of these new compounds from a new, chemically rich genus further documents that marine actinomycetes are a significant resource for drug discovery.