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2018
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.

Leutou, AS, Yang IH, Le TC, Hahn D, Lim KM, Nam SJ, Fenical W.  2018.  Fluvirucin B6, a new macrolactam isolated from a marine-derived actinomycete of the genus Nocardiopsis. Journal of Antibiotics. 71:609-612.   10.1038/s41429-018-0033-3   AbstractWebsite

A new 14-membered macrolactam natural product, fluvirucin B6 (1), was isolated from a marine-derived actinomycete, Nocardiopsis sp. CNQ-115, via HPLC-UV guided isolation. The chemical structure of 1 was elucidated by 1D and 2D NMR spectroscopic data analysis. Compound 1 showed a weak activity against Gram-positive bacteria, whereas it was inactive against Gram-negative bacteria.

da Silva, RM, Guaratini T, Jimenez PC, Fenical W, Costa-Lotufo LV, Vessecchi R, Lopes NP.  2018.  Mass spectrometry analysis of protonated marine natural product seriniquinone. Journal of the Brazilian Chemical Society. 29:1162-1166.   10.21577/0103-5053.20180037   AbstractWebsite

Seriniquinone is a natural quinone isolated from a rare marine bacterium of the genus Serinicoccus. This secondary metabolite has been shown to have anticancer properties, which has raised attention of the scientific community. In this short report, we present the first investigation of the gas-phase chemistry fragmentation reactions of seriniquinone in electrospray ionization tandem mass spectrometry (ESI-MS/MS), to be further applied in pharmacokinetics and metabolism studies. All the proposals herein were supported by computational chemistry.

Zheng, J, McKinnie SMK, El Gama A, Fengit W, Dong Y, Agarwal V, Fenical W, Kumar A, Cao ZY, Moore BS, Pessah IN.  2018.  Organohalogens naturally biosynthesized in marine environments and produced as disinfection byproducts alter sarco/endoplasmic reticulum ca2+ dynamics. Environmental Science & Technology. 52:5469-5478.   10.1021/acs.est.8b00512   AbstractWebsite

Contemporary sources of organohalogens produced as disinfection byproducts (DBPs) are receiving considerable attention as emerging pollutants because of their abundance, persistence, and potential to structurally mimic natural organohalogens produced by bacteria that serve signaling or toxicological functions in marine environments. Here, we tested 34 organohalogens from anthropogenic and marine sources to identify compounds active toward ryanodine receptor (RyR1), known toxicological targets of non-dioxin like polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). [H-3]Ryanodine ([H-3]Ry) binding screening (<= 2 mu M) identified 10 highly active organohalogens. Further analysis indicated that 2,3-dibromoindole (14), tetrabromopyrrole (31), and 2,3,S-tribromopyrrole (34) at 10 mu M were the most efficacious at enhancing [H-3]Ry binding. Interestingly, these congeners also inhibited microsomal sarcoplasmic/endoplasmic reticulum (SR/ER) Ca2+ ATPase (SERCA1a). Dual SERCAla inhibition and RyR1 activation triggered Ca2+ efflux from microsomal vesicles with initial rates rank ordered 31 > 34 > 14. Hexabromobipyrroles (25) enhanced [H-3]Ry binding moderately with strong SERCAla inhibition, whereas pyrrole (24), 2,3,4-tribromopyrrole (26), and ethyl-4-bromopyrrole-2-carboxylate (27) were inactive. Of three PBDE derivatives of marine origin active in the [H-3]Ry assay, 4'-hydroxy-2,3',4,5',6-pentabromodiphenyl ether (18) was also a highly potent SERCAla inhibitor. Molecular targets of marine organohalogens that are also DBPs of emerging environmental concern are likely to contribute to their toxicity.

Nakatsuji, T, Chen TH, Butcher AM, Trzoss LL, Nam SJ, Shirakawa KT, Zhou W, Oh J, Otto M, Fenical W, Gallo RL.  2018.  A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Science Advances. 4   10.1126/sciadv.aao4502   AbstractWebsite

We report the discovery that strains of Staphylococcus epidermidis produce 6-N-hydroxyaminopurine ( 6-HAP), a molecule that inhibits DNA polymerase activity. In culture, 6-HAP selectively inhibited proliferation of tumor lines but did not inhibit primary keratinocytes. Resistance to 6-HAP was associated with the expression of mitochondrial amidoxime reducing components, enzymes that were not observed in cells sensitive to this compound. Intravenous injection of 6-HAP in mice suppressed the growth of B16F10 melanoma without evidence of systemic toxicity. Colonization of mice with an S. epidermidis strain producing 6-HAP reduced the incidence of ultraviolet-induced tumors compared to mice colonized by a control strain that did not produce 6-HAP. S. epidermidis strains producing 6-HAP were found in the metagenome from multiple healthy human subjects, suggesting that the microbiome of some individuals may confer protection against skin cancer. These findings show a new role for skin commensal bacteria in host defense.

2017
Amos, GCA, Awakawa T, Tuttle RN, Letzel AC, Kim MC, Kudo Y, Fenical W, Moore BS, Jensen PR.  2017.  Comparative transcriptomics as a guide to natural product discovery and biosynthetic gene cluster functionality. Proceedings of the National Academy of Sciences of the United States of America. 114:E11121-E11130.   10.1073/pnas.1714381115   AbstractWebsite

Bacterial natural products remain an important source of new medicines. DNA sequencing has revealed that a majority of natural product biosynthetic gene clusters (BGCs) maintained in bacterial genomes have yet to be linked to the small molecules whose biosynthesis they encode. Efforts to discover the products of these orphan BGCs are driving the development of genome mining techniques based on the premise that many are transcriptionally silent during normal laboratory cultivation. Here, we employ comparative transcriptomics to assess BGC expression among four closely related strains of marine bacteria belonging to the genus Salinispora. The results reveal that slightly more than half of the BGCs are expressed at levels that should facilitate product detection. By comparing the expression profiles of similar gene clusters in different strains, we identified regulatory genes whose inactivation appears linked to cluster silencing. The significance of these subtle differences between expressed and silent BGCs could not have been predicted a priori and was only revealed by comparative transcriptomics. Evidence for the conservation of silent clusters among a larger number of strains for which genome sequences are available suggests they may be under different regulatory control from the expressed forms or that silencing may represent an underappreciated mechanism of gene cluster evolution. Coupling gene expression and metabolomics data established a bioinformatic link between the salinipostins and their associated BGC, while genetic manipulation established the genetic basis for this series of compounds, which were previously unknown from Salinispora pacifica.

Yim, CY, Le TC, Lee TG, Yang I, Choi H, Lee J, Kang KY, Lee JS, Lim KM, Yee ST, Kang H, Nam SJ, Fenical W.  2017.  Saccharomonopyrones A-C, New alpha-Pyrones from a Marine Sediment-Derived Bacterium Saccharomonospora sp CNQ-490. Marine Drugs. 15   10.3390/md15080239   AbstractWebsite

Intensive study of the organic extract of the marine-derived bacterium Saccharomonospora sp. CNQ-490 has yielded three new ff-pyrones, saccharomonopyrones A-C (1-3). The chemical structures of these compounds were assigned from the interpretation of 1D, 2D NMR and mass spectrometry data. Saccharomonopyrone A (1) is the first ff -pyrone microbial natural product bearing the ethyl-butyl ether chain in the molecule, while saccharomonopyrones B and C possess unusual 3-methyl and a 6-alkyl side-chain within a 3,4,5,6-tetrasubstituted alpha-pyrone moiety. Saccharomonopyrone A exhibited weak antioxidant activity using a cation radical scavenging activity assay with an IC50 value of 140 mu M.

Le, TC, Yim CY, Park S, Katila N, Yang I, Song MC, Yoon YJ, Choi DY, Choi H, Nam SJ, Fenical W.  2017.  Lodopyridones B and C from a marine sediment-derived bacterium Saccharomonospora sp. Bioorganic & Medicinal Chemistry Letters. 27:3123-3126.   10.1016/j.bmcl.2017.05.035   AbstractWebsite

HPLC-UV guided isolation of the culture broth of a marine bacterium Saccharomonospora sp. CNQ-490 has led to the isolation of two new natural products, lodopyridones B and C (1 and 2) along with the previously reported lodopyridone A (3). Their chemical structures were established from the interpretation of 2D NMR spectroscopic data and the comparison of NMR data with the lodopyridone A (3). Lodopyridones B and C (1 and 2) possess the thiazole, and chloroquinoline groups which are characteristic features of these molecules. Lodopyridones A-C show weak inhibitory activities on the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). (c) 2017 Elsevier Ltd. All rights reserved.

Yang, I, Yoon J, Kim D, Hahn D, Nam SJ, Fenical W.  2017.  4Z- and 4E-12-deoxydihydrokromycins, two naturally occurring kromycin aglycones of pikromycin from Streptomyces sp. Tetrahedron Letters. 58:2322-2324.   10.1016/j.tetlet.2017.03.088   AbstractWebsite

HPLC-UV guided isolation for the culture broth extract of the marine-derived bacterium Streptomyces sp. has led to the two 14-membered macrolides, 4Z- (1) and 4E-12-dehydroxykromycins (2). The chemical structures of compounds 1 and 2 were elucidated by spectral data, while the absolute stereochemistry of 1 and 2 were determined by application of circular dichroism (CD) and analysis of X-ray crystallographic data. (C) 2017 Published by Elsevier Ltd.

Asolkar, RN, Singh A, Jensen PR, Aalbersberg W, Carte BK, Feussner KD, Subramani R, DiPasquale A, Rheingold AL, Fenical W.  2017.  Marinocyanins, cytotoxic bromo-phenazinone meroterpenoids from a marine bacterium from the streptomycete Glade MAR4. Tetrahedron. 73:2234-2241.   10.1016/j.tet.2017.03.003   AbstractWebsite

Six cytotoxic and antimicrobial metabolites of a new bromo-phenazinone class, the marinocyanins A-F (1-6), were isolated together with the known bacterial metabolites 2-bromo-1-hydroxyphenazine (7), lavanducyanin (8, WS-9659A) and its chlorinated analog WS-9659B (9). These metabolites were purified by bioassay-guided fractionation of the extracts of our MAR4 marine actinomycete strains CNS-284 and CNY-960. The structures of the new compounds were determined by detailed spectroscopic methods and marinocyanin A (1) was confirmed by crystallographic methods. The marinocyanins represent the first bromo-phenazinones with an N-isoprenoid substituent in the skeleton. Marinocyanins A-F show strong to weak cytotoxicity against HCT-116 human colon carcinoma and possess modest antimicrobial activities against Staphylococcus aureus and amphotericin-resistant Candida albicans. (C) 2017 Elsevier Ltd. All rights reserved.

Lee, HW, Choi H, Nam SJ, Fenical W, Kim H.  2017.  Potent Inhibition of Monoamine Oxidase B by a Piloquinone from Marine-Derived Streptomyces sp CNQ-027. Journal of Microbiology and Biotechnology. 27:785-790.   10.4014/jmb.1612.12025   AbstractWebsite

Two piloquinone derivatives isolated from Streptomyces sp. CNQ-027 were tested for the inhibitory activities of two isoforms of monoamine oxidase (MAO), which catalyzes monoamine neurotransmitters. The piloquinone 4,7-dihydroxy-3-methyl-2-(4-methyl-1-oxopentyl)-6H-dibenzo[b,d]pyran-6-one (1) was found to be a highly potent inhibitor of human MAO-B, with an IC50 value of 1.21 mu M; in addition, it was found to be highly effective against MAO-A, with an IC50 value of 6.47 mu M. Compound 1 was selective, but not extremely so, for MAO-B compared with MAO-A, with a selectivity index value of 5.35. Compound 1,8-dihydroxy-2-methyl-3-(4-methyl-1-oxopentyl)-9,10-phenanthrenedione (2) was moderately effective for the inhibition of MAO-B (IC50 = 14.50 mu M) but not for MAO-A (IC50 > 80 mu M). There was no time-dependency in inhibition of MAO-A or -B by compound 1, and the MAO-A and -B activities were almost completely recovered in the dilution experiments with an excess amount of compound 1. Compound 1 showed competitive inhibition for MAO-A and -B, with K-i values of 0.573 and 0.248 mu M, respectively. These results suggest that piloquinones from a microbial source could be potent reversible MAO inhibitors and may be useful lead compounds for developing MAO enzyme inhibitors to treat related disorders, such as depression, Parkinson's disease, and Alzheimer's disease.

Hay, AJ, Yang MH, Xia XY, Liu Z, Hammons J, Fenical W, Zhu J.  2017.  Calcium enhances bile salt-dependent virulence activation in Vibrio cholerae. Infection and Immunity. 85   10.1128/iai.00707-16   AbstractWebsite

Vibrio cholerae is the causative bacteria of the diarrheal disease cholera, but it also persists in aquatic environments, where it displays an expression profile that is distinct from that during infection. Upon entry into the host, a tightly regulated circuit coordinates the induction of two major virulence factors: cholera toxin and a toxin-coregulated pilus (TCP). It has been shown that a set of bile salts, including taurocholate, serve as host signals to activate V. cholerae virulence through inducing the activity of the transmembrane virulence regulator TcpP. In this study, we investigated the role of calcium, an abundant mental ion in the gut, in the regulation of virulence. We show that whereas Ca2+ alone does not affect virulence, Ca2+ enhances bile salt-dependent virulence activation for V. cholerae. The induction of TCP by murine intestinal contents is counteracted when Ca2+ is depleted by the high-affinity calcium chelator EGTA, suggesting that the calcium present in the gut is a relevant signal for V. cholerae virulence induction in vivo. We further show that Ca2+ enhances virulence by promoting bile salt-induced TcpP-TcpP interaction. Moreover, fluorescence recovery after photobleaching (FRAP) analysis demonstrated that exposure to bile salts and Ca2+ together decreases the recovery rate for fluorescently labeled TcpP, but not for another inner membrane protein (TatA). Together, these data support a model in which physiological levels of Ca2+ may result in altered bile salt-induced TcpP protein movement and activity, ultimately leading to an increased expression of virulence.

Kumar, A, Borgen M, Aluwihare LI, Fenical W.  2017.  Ozone-activated halogenation of mono- and dimethylbipyrrole in seawater. Environmental Science & Technology. 51:589-595.   10.1021/acs.est.6b03601   AbstractWebsite

Polyhalogenated N-methylbipyrroles of two different structure classes have been detected worldwide in over 100 environmental samples including seawater, bird eggs, fish, dolphin blubber, and in the breast milk of humans that consume seafood. These molecules are concentrated in the fatty tissues in comparable abundance to some of the most important anthropogenic contaminants, such as the halogenated flame-retardants and pesticides. Although the origin of these compounds is still unknown, we present evidence that the production of these materials can involve the direct ozone activated seawater halogenation of N-methylbipyrrole precursors. This observation shows that environmental polyhalogenated bipyrroles can be produced via an abiotic process, and implies that the ozone activated halogenation of a variety of natural and anthropogenic seawater organics may be a significant process occurring in surface ocean waters.

2016
Beuzer, P, Axelrod J, Trzoss L, Fenical W, Dasari R, Evidente A, Kornienko A, Cang H, La Clair JJ.  2016.  Single dish gradient screening of small molecule localization. Organic & Biomolecular Chemistry. 14:8241-8245.   10.1039/c6ob01418f   AbstractWebsite

Understanding trafficking in cells and tissues is one of the most critical steps in exploring the mechanisms and modes of action (MOAs) of a small molecule. Typically, deciphering the role of concentration presents one of the most difficult challenges associated with this task. Herein, we present a practical solution to this problem by developing concentration gradients within single dishes of cells. We demonstrate the method by evaluating fluorescently-labelled probes developed from two classes of natural products that have been identified as potential anti-cancer leads by STORM super-resolution microscopy.

La Clair, JJ, Fenical W, Costa-Lotufo LV.  2016.  Elucidating the mode of action of marine natural products through an immunoaffinity fluorescent (iaf) approach. Journal of the Brazilian Chemical Society. 27:1346-1354.   10.5935/0103-5053.20160148   AbstractWebsite

Understanding the target and mode of action (MOA) of small molecules activity has become a critical feature in guiding the transition between drug discovery and clinical evaluation. While classically placed at the latter stages of a discovery program, we now describe how addressing the mode of action of natural products at the early stages of a program provides an important vehicle to inform the drug discovery process. In this review, we outline a streamlined cellular and molecular biological system and explore its utility through a series of four cases studies. We believe that this approach offers critical lessons to guide future drug discovery programs.

Zhou, XF, Fenical W.  2016.  The unique chemistry and biology of the piericidins. Journal of Antibiotics. 69:582-593.   10.1038/ja.2016.7   AbstractWebsite

The piericidin family of microbial metabolites features a 4-pyridinol core linked with a methylated polyketide side chain. Piericidins are exclusively produced by actinomycetes, especially members of the genus Streptomyces. The close structural similarity with coenzyme Q renders the piericidins important NADH-ubiquinone oxidoreductase (complex I) inhibitors in the mitochondria! electron transport chain. Because of the significant activities of the piericidins, which include insecticidal, antimicrobial and antitumor effects, total syntheses of the piericidins were developed using various synthetic strategies. The biosynthetic origin of this class has also been the subject of investigation. This review covers the isolation and structure determination of the natural piericidins, their chemical modification, the total syntheses of natural and unnatural analogs, their biosynthesis, and reported biological activities together with structure-activity relationships. Given the fundamental biology of this class of metabolites, the piericidin family will likely continue to attract attention as biological probes of important biosynthetic processes.

Hassan, HM, Boonlarppradab C, Fenical W.  2016.  Actinoquinolines A and B, anti-inflammatory quinoline alkaloids from a marine-derived Streptomyces sp., strain CNP975. Journal of Antibiotics. 69:511-514.   10.1038/ja.2016.56   AbstractWebsite

Actinomycete bacteria of the common genus Streptomyces can be routinely isolated from shallow and deep ocean sediments. Although commonly considered a terrestrial genus, and most abundantly found in soil, Streptomyces strains are found that have distinct requirements for seawater and routinely do not show significant similarity, with terrestrial strains by 16S ribosomal DNA phylogenetic sequence comparisons. Our examination of the culture broth of a Streptomyces sp., strain CNP975, isolated from a local La Jolla, California sediment sample, resulted in the isolation of actinoquinolines A and B (1, 2), which show significant inhibition of the arachidonic acid pathway enzymes cyclooxygenases-1 and -2. The new compounds contain the 3-hydroxyquinaldic acid (3HQA) motif found in numerous peptide antibiotics. In the actinoquinolines, 3HQA forms an amide linkage with a linear six-carbon fragment, formally a 2, 6-diamino-1, 5-dihydroxyhexane unit, a component of likely amino acid reductive off-loading origin. Actinoquinoline A illustrated amide rotational isomerism leading to complex NMR spectral data. Actinoquinoline B was assigned as the C-13 aldehyde analog isolated as an intramolecular hemiacetal. Reduction of 2 with NaBH4 yielded actinoquinoline A thus confirming the relative configurations of all centers in the actinoquinolines.

Le, TC, Yang I, Yoon YJ, Nam SJ, Fenical W.  2016.  Ansalactams B-D illustrate further biosynthetic plasticity within the ansamycin pathway. Organic Letters. 18:2256-2259.   10.1021/acs.orglett.6b00892   AbstractWebsite

Further chemical investigation of a marine-derived bacterium of the genus Streptomyces has led to the isolation of ansalactams B-D (1-3) along with the previously reported metabolite ansalactam A (4). Ansalactams B-D are significantly modified ansamycins, representing three new carbon skeletons and further illustrating the biosynthetic plasticity of the ansalactam class. Unlike ansalactam A, ansalactams B and D are penta- and hexacyclic metabolites, while ansalactam C illustrates an open polyene chain with a terminal carboxylic acid.

Lee, J, Han C, Lee TG, Chin J, Choi H, Lee W, Paik MJ, Won DH, Jeong G, Ko J, Yoong YJ, Nam SJ, Fenical W, Kang H.  2016.  Marinopyrones A-D, alpha-pyrones from marine-derived actinomycetes of the family Nocardiopsaceae. Tetrahedron Letters. 57:1997-2000.   10.1016/j.tetlet.2016.03.084   AbstractWebsite

Two actinomycetes, a member of the rare halophilic genus Streptomonospora and a Nocardiopsis sp. (Nocardiopsaceae), strains CNQ-082 and CNQ-675, respectively, were isolated from marine sediments collected off shore near La Jolla, California. HPLC-UV guided fractionations of the extracts of these strains yielded marinopyrones A-D (1-4), the structures of which were elucidated by interpretation of 1D and 2D NMR and HRMS spectroscopic data. Oxidative ozonation, followed by conversion of the acid product to an alpha-naphthyl amide, provided the absolute configuration at the chiral center on the side-chain. Marinopyrones A-D were examined for the inhibitory activity on nitric oxide production in LPS-activated mouse macrophage cells (RAW 264.7); marinopyrone D (4) was inhibitory with an IC50 value of 13 mu M. To our knowledge, marinopyrones A-C are only the second reported natural products from the rare halophilic genus Streptomonospora. (C) 2016 Elsevier Ltd. All rights reserved.

2015
Ruckert, C, Leipoldt F, Zeyhle P, Fenical W, Jensen PR, Kalinowski J, Heide L, Kaysser L.  2015.  Complete genome sequence of Streptomyces sp CNQ-509, a prolific producer of meroterpenoid chemistry. Journal of Biotechnology. 216:140-141.   10.1016/j.jbiotec.2015.08.009   AbstractWebsite

Streptomyces sp. CNQ-509 is a marine actinomycete belonging to the MAR4 streptomycete lineage. MAR4 strains have been linked to the production of diverse and otherwise rare meroterpenoid compounds. The genome sequence of Streptomyces sp. CNQ-509 was found to contain 29 putative gene clusters for the biosynthesis of secondary metabolites, some of them potentially involved in the formation of meroterpenoid molecules. (C) 2015 Elsevier B.V. All rights reserved.

Puyana, M, Pawlik J, Blum J, Fehical W.  2015.  Metabolite variability Caribbean sponges of the genus Aplysina. Revista Brasileira De Farmacognosia-Brazilian Journal of Pharmacognosy. 25:592-599.   10.1016/j.bjp.2015.08.002   AbstractWebsite

Sponges of the genus Aplysina are among the most common benthic animals on reefs of the Caribbean, and display a wide diversity of morphologies and colors. Tissues of these sponges lack mineralized skeletal elements, but contain a dense spongin skeleton and an elaborate series of tyrosine-derived brominated alkaloid metabolites that function as chemical defenses against predatory fishes, but do not deter some molluscs. Among the earliest marine natural products to be isolated and identified, these metabolites remain the subject of intense interest for commercial applications because of their activities in various bioassays. In this study, crude organic extracts from 253 sponges from ten morphotypes among the species Aplysina archeri, Aplysina bathyphila, Aplysina cauliformis, Aplysina fistularis, Aplysina fulva, A. insularis, and Aplysina lacunosa were analyzed by liquid chromatographymass spectrometry (LCMS) to characterize the pattern of intra- and interspecific variabilities of the twelve major secondary metabolites present therein. Patterns across Aplysina species ranged from the presence of mostly a single compound, fistularin-3, in A. cauliformis, to a mixture of metabolites present in the other species. These patterns did not support the biotransformation hypothesis for conversion of large molecular weight molecules to smaller ones for the purpose of enhanced defense. Discriminant analyses of the metabolite data revealed strong taxonomic patterns that support a close relationship between A. fistularis, A. fulva and A. insularis, while two morphotypes of A. cauliformis (lilac creeping vs. brown erect) were very distinct. Two morphotypes of A. lacunosa, one with hard tissue consistency, the other soft and thought to belong to a separate genus (Suberea), had very similar chemical profiles. Of the twelve metabolites found among samples, variation in fistularin-3, dideoxyfistularin-3 and hydroxyaerothionin provided the most predictive influence in decreasing order. Except for one morphotype, weak relationships were found from within-morphotype analyses of metabolite concentrations as a function of geographic location (Florida, N Bahamas, S Bahamas) and depth (<10m, 1020m, >20m). Our data suggest that metabolite profiles are strongly influenced by sponge phenotype rather than by the diverse microbiome which many Aplysina species share. (C) 2015 Sociedade Brasileira de Earmacognosia. Published by Elsevier Editora Ltda. All rights reserved.

Leutou, AS, Yang I, Kang H, Seo EK, Nam SJ, Fenical W.  2015.  Nocarimidazoles A and B from a marine-derived actinomycete of the genus Nocardiopsis. Journal of Natural Products. 78:2846-2849.   10.1021/acs.jnatprod.5b00746   AbstractWebsite

Chemical investigation of a marine-derived actinomycete isolated from marine sediments collected off the coast of southern California and identified as a Nocardiopsis sp. (strain CNQ115) led to the isolation of two new 4-aminoimidazole alkaloids, nocarimidazoles A (1) and B (2). The chemical structures of nocarimidazoles A and B were assigned by interpretation of NMR spectroscopic data and through methylation to yield monomethyl and dimethyl derivatives. Nocarimidazoles A and B possess a 4-aminoimidazole ring combined with a conjugated carbonyl side chain, which is rarely found in microbial secondary metabolites.

Jungmann, K, Jansen R, Gerth K, Huch V, Krug D, Fenical W, Muller R.  2015.  Two of a kind: The biosynthetic pathways of chlorotonil and anthracimycin. Acs Chemical Biology. 10:2480-2490.   10.1021/acschembio.5b00523   AbstractWebsite

Chlorotonil A is a novel polyketide isolated from the myxobacterium Sorangium cellulosum So ce1525 that features a unique gem-dichloro-1,3-dione moiety. It exhibits potent bio-activity, most notably against the problematic malaria pathogen Plasmodium falciparum in the nanomolar range. In addition, strong antibacterial and Moderate antifungal activity were determined. The outstanding biological activity of chlorotonil A as well as its unusual chemical structure triggered our interest in elucidating 18 biosynthesis, a:prerequisite for alteration of the scaffold by synthetic biology approaches. This endeavor was facilitated by a recent report describing the strikingly similar structure of anthracimycin from a marine streptomycete, a compound of considerable interest due to its potent antibacterial activity. In this study, we report the identification and characterization of the chlorotonil A biosynthetic gene cluster from So ce1525 and compare It with that for anthracimycin biosynthesis. Access to both gene dusters allowed us to highlight commonalities between the two pathways and revealed striking differences, some of which Can plausibly;explain the structural differences observed between these intriguing natural products.

Alvarez-Mico, X, Rocha DD, Guimaraes LA, Ambrose A, Chapman E, Costa-Lotufo LV, La Clair JJ, Fenical W.  2015.  The hybrid pyrroloisoindolone-dehydropyrrolizine alkaloid (-)-chlorizidine a targets proteins within the glycolytic pathway. Chembiochem. 16:2002-2006.   10.1002/cbic.201500229   AbstractWebsite

The cytotoxic activity of (-)-chlorizidine A, a marine alkaloid containing a unique fusion between a pyrroloisoindolone and dehydropyrrolizine, was explored by using a combination of cellular and molecular methods. Our studies began by applying preliminary SAR evidence gathered from semisynthetic bioactivity evaluations to prepare an active immunoaffinity fluorescent (IAF) probe. This probe was then used to identify two cytosolic proteins, GAPDH and hENO1, as the targets of (-)chlorizidine A.

Choi, EJ, Nam SJ, Paul L, Beatty D, Kauffman CA, Jensen PR, Fenical W.  2015.  Previously uncultured marine bacteria linked to novel alkaloid production. Chemistry & Biology. 22:1270-1279.   10.1016/j.chembiol.2015.07.014   AbstractWebsite

Low-nutrient media and long incubation times facilitated the cultivation of 20 taxonomically diverse Gram-negative marine bacteria within the phyla Bacteroidetes and Proteobacteria. These strains comprise as many as three new families and include members of clades that had only been observed using culture-independent techniques. Chemical studies of the type strains representing two new families within the order Cytophagales led to the isolation of nine new alkaloid secondary metabolites that can be grouped into four distinct structure classes, including azepinones, aziridines, quinolones, and pyrazinones. Several of these compounds possess antibacterial properties and appear, on structural grounds, to be produced by amino acid-based biosynthetic pathways. Our results demonstrate that relatively simple cultivation techniques can lead to the isolation of new bacterial taxa that are capable of the production of alkaloid secondary metabolites with antibacterial activities. These findings support continued investment in cultivation techniques as a method for natural product discovery.