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Sakoulas, G, Nam SJ, Loesgen S, Fenical W, Jensen PR, Nizet V, Hensler M.  2012.  Novel Bacterial Metabolite Merochlorin A Demonstrates in vitro Activity against Multi-Drug Resistant Methicillin-Resistant Staphylococcus aureus. Plos One. 7   10.1371/journal.pone.0029439   AbstractWebsite

Background: We evaluated the in vitro activity of a merochlorin A, a novel compound with a unique carbon skeleton, against a spectrum of clinically relevant bacterial pathogens and against previously characterized clinical and laboratory Staphylococcus aureus isolates with resistance to numerous antibiotics. Methods: Merochlorin A was isolated and purified from a marine-derived actinomycete strain CNH189. Susceptibility testing for merochlorin A was performed against previously characterized human pathogens using broth microdilution and agar dilution methods. Cytotoxicity was assayed in tissue culture assays at 24 and 72 hours against human HeLa and mouse sarcoma L929 cell lines. Results: The structure of as new antibiotic, merochlorin A, was assigned by comprehensive spectroscopic analysis. Merochlorin A demonstrated in vitro activity against Gram-positive bacteria, including Clostridium dificile, but not against Gram negative bacteria. In S. aureus, susceptibility was not affected by ribosomal mutations conferring linezolid resistance, mutations in dlt or mprF conferring resistance to daptomycin, accessory gene regulator knockout mutations, or the development of the vancomycin-intermediate resistant phenotype. Merochlorin A demonstrated rapid bactericidal activity against MRSA. Activity was lost in the presence of 20% serum. Conclusions: The unique meroterpenoid, merochlorin A demonstrated excellent in vitro activity against S. aureus and C. dificile and did not show cross-resistance to contemporary antibiotics against Gram positive organisms. The activity was, however, markedly reduced in 20% human serum. Future directions for this compound may include evaluation for topical use, coating biomedical devices, or the pursuit of chemically modified derivatives of this compound that retain activity in the presence of serum.

Schorn, MA, Alanjary MM, Aguinaldo K, Korobeynikov A, Podell S, Patin N, Lincecum T, Jensen PR, Ziemert N, Moore BS.  2016.  Sequencing rare marine actinomycete genomes reveals high density of unique natural product biosynthetic gene clusters. Microbiology-Sgm. 162:2075-2086.   10.1099/mic.0.000386   AbstractWebsite

Traditional natural product discovery methods have nearly exhausted the accessible diversity of microbial chemicals, making new sources and techniques paramount in the search for new molecules. Marine actinomycete bacteria have recently come into the spotlight as fruitful producers of structurally diverse secondary metabolites, and remain relatively untapped. In this study, we sequenced 21 marine-derived actinomycete strains, rarely studied for their secondary metabolite potential and under-represented in current genomic databases. We found that genome size and phylogeny were good predictors of biosynthetic gene cluster diversity, with larger genomes rivalling the well-known marine producers in the Streptomyces and Salinispora genera. Genomes in the Micrococcineae suborder, however, had consistently the lowest number of biosynthetic gene clusters. By networking individual gene clusters into gene cluster families, we were able to computationally estimate the degree of novelty each genus contributed to the current sequence databases. Based on the similarity measures between all actinobacteria in the Joint Genome Institute's Atlas of Biosynthetic gene Clusters database, rare marine genera show a high degree of novelty and diversity, with Corynebacterium, Gordonia, Nocardiopsis, Saccharomonospora and Pseudonocardia genera representing the highest gene cluster diversity. This research validates that rare marine actinomycetes are important candidates for exploration, as they are relatively unstudied, and their relatives are historically rich in secondary metabolites.

Schultz, AW, Oh DC, Carney JR, Williamson RT, Udwary DW, Jensen PR, Gould SJ, Fenical W, Moore BS.  2008.  Biosynthesis and structures of cyclomarins and cyclomarazines, prenylated cyclic peptides of marine actinobacterial origin. Journal of the American Chemical Society. 130:4507-4516.   10.1021/ja711188x   AbstractWebsite

Two new diketopiperazine dipeptides, cyclomarazines A and B, were isolated and characterized along with the new cyclic heptapeptide cyclomarin D from the marine bacterium Salinispora arenicola CNS-205. These structurally related cyclic peptid es each contain modified amino acid residues, including derivatives of N-(1,1-dimethylallyl)-tryptophan and delta-hydroxyleucine, which are common in the di- and heptapeptide series. Stable isotope incorporation studies in Streptomyces sp. CNB-982, which was first reported to produce the cyclomarin anti-inflammatory agents, illuminated the biosynthetic building blocks associated with the major metabolite cyclomarin A, signifying that this marine microbial peptide is nonribosomally derived largely from nonproteinogenic amino acid residues. DNA sequence analysis of the 5.8 Mb S. arenicola circular genome and PCR-targeted gene inactivation experiments identified the 47 kb cyclomarin/cyclomarazine biosynthetic gene cluster (cym) harboring 23 open reading frames. The cym locus is dominated by the 23 358 bp cymA, which encodes a 7-module nonribosomal pepticle synthetase (NRPS) responsible for assembly of the full-length cyclomarin heptapeptides as well as the truncated cyclomarazine dipeptides. The unprecedented biosynthetic feature of the megasynthetase CymA to synthesize differently sized peptides in vivo may be triggered by the level of P oxidation of the priming tryptophan residue, which is oxidized in the cyclomarin series and unoxidized in the cyclomarazines. Biosynthesis of the N-(1;1-dimethyl-2,3-epoxypropyl)-beta-hydroxytryptophan residue of cyclomarin A was further illuminated through gene inactivation experiments, which suggest that the tryptophan residue is reverse prenylated by CymD prior to release of the cyclic peptide from the CymA megasynthetase, whereas the cytochrome P450 CymV installs the epoxide group on the isoprene of cyclomarin C post-NRPS assembly. Last, the novel amino acid residue 2-amino-3,5-dimethylhex-4-enoic acid in the cyclomarin series was shown by bioinformatics and stable isotope experiments to derive from a new pathway involving condensation of isobutyralclehyde and pyruvate followed by S-adenosylmethionine methylation. Assembly of this unsaturated, branched amino acid is unexpectedly related to the degradation of the environmental pollutant 3-(3-hydroxyphenyl)propionic acid.

Son, BW, Jensen PR, Kauffman CA, Fenical W.  1999.  New cytotoxic epidithiodioxopiperazines related to verticillin A from a marine isolate of the fungus Penicillium. Natural Product Letters. 13:213-222.   10.1080/10575639908048788   AbstractWebsite

Two new cytotoxic dioxopiperazine dimers, 11,11'-dideoxyverticillin A (1) and 11'-deoxyverticillin A (2), and the previously described verticillin A (3), have been isolated from the mycelium of a marine-derived fungus of the genus Penicillium. An inactive, but new bisdethio-bis(methylthio)-dioxopiperazine 4, was also obtained by extraction of the culture broth. The structures and absolute stereochemistries of the new compounds were assigned on the basis of NMR and CD experiments. Compounds 1 and 2 exhibit potent in vitro cytotoxicity against HCT-116 human colon carcinoma (IC50 = 30 ng/ml).

Soria-Mercado, IE, Jensen PR, Fenical W, Kassel S, Golen J.  2004.  3,4a-Dichloro-10a-(3-chloro-6-hydroxy-2,2,6-trimethylcyclohexylmethyl)-6 ,8-dihydroxy-2,2,7-trimethyl-3,4,4a,10a-tetrahydro-2H-benzo g chromene-5 ,10-dione. Acta Crystallographica Section E-Structure Reports Online. 60:O1627-O1629.   10.1107/s1600536804020094   AbstractWebsite

The title microbial antibiotic, C26H33Cl3O6, is an unusual trichlorinated dihydroquinone with cyclized prenyl and geranyl terpene substitution. The crystal structure provides an unambiguous assignment for this compound including its absolute stereochemistry, and shows the favored configuration of the chlorocyclohexane substituent.

Soria-Mercado, IE, Prieto-Davo A, Jensen PR, Fenical W.  2005.  Antibiotic terpenoid chloro-dihydroquinones from a new marine actinomycete. Journal of Natural Products. 68:904-910.   10.1021/np058011z   AbstractWebsite

As part of our continuing interest in exploring the chemistry of actinomycete bacteria uniquely adapted for survival in ocean sediments, we encountered several new strains, which by 16S rDNA sequence-based phylogenetic analysis were recognized as members of a new genus (tentatively called MAR4) within the family Streptomycetaceae. We report here the isolation and structure elucidation of three new chlorinated dihydroquinones (1-3) and one previously reported analogue, 4, from our strain CNQ-525, isolated from ocean sediments collected at a depth of 152 m near La Jolla, California. The compounds formally possess new carbon skeletons, but are related to several previously reported metabolites of the napyradiomycin class. The structures of the new molecules, which possess significant antibiotic properties and cancer cell cytotoxicities, were assigned by comprehensive spectral measurements and by comparison with NMR and other spectral data from the antibiotic A80915C (5), the full stereostructure of which was recently assigned by X-ray diffraction methods.

Spyere, A, Rowley DC, Jensen PR, Fenical W.  2003.  New neoverrucosane diterpenoids produced by the marine gliding bacterium Saprospira grandis. Journal of Natural Products. 66:818-822.   10.1021/np0205351   AbstractWebsite

Chemical examination of the culture broth extracts of the marine gliding bacterium Saprospira grandis (ATCC 23116) has resulted in the isolation of four new diterpenoids of the neoverrucosane class. The structures of the new diterpenoids, compounds 1-4, were assigned by combined spectroscopic methods emphasizing 2D NMR experiments. The relative stereochemistry of 1 was determined by 2D ROESY NMR methods, while the absolute stereochemistry was assigned by application of the modified Mosher method. This study adds to the rare observation of terpene production by prokaryotic microorganisms and suggests that marine gliding bacteria may be a significant source for new terpenoid secondary metabolites.

Strangman, WK, Kwon HC, Broide D, Jensen PR, Fenical W.  2009.  Potent Inhibitors of Pro-Inflammatory Cytokine Production Produced by a Marine-Derived Bacterium. Journal of Medicinal Chemistry. 52:2317-2327.   10.1021/jm801110j   AbstractWebsite

Cytokines produced through the antigen presenting cell (APC)-T-cell interaction play a key role in the activation of the allergic asthmatic response. Evaluating small molecules that inhibit the production of these pro-inflammatory proteins is therefore important for the discovery of novel chemical structures with potential antiasthma activity. We adapted a mouse splerrocyte cytokine assay to screen a library of 2,500 marine microbial extracts for their ability to inhibit T(H)2 cytokine release and identified potent activity in a marine-derived strain CNQ431, identified as a Streptomyces species. Bioactivity guided fractionation of the organic extract of this strain led to the isolation of ten new 9-membered bis-lactones, splenocins A-J (1-10). The new compounds display potent biological activities, comparable to that of the corticosteroid dexamethasone, with IC(50) values from 2 to 50 nM in the splenocyte cytokine assay. This study provides the foundation for the optimization of these potent anti-inflammatory compounds for development in the treatment of asthma.

Sun, P, Maloney KN, Nam SJ, Haste NM, Raju R, Aalbersberg W, Jensen PR, Nizet V, Hensler ME, Fenical W.  2011.  Fijimycins A-C, three antibacterial etamycin-class depsipeptides from a marine-derived Streptomyces sp. Bioorganic & Medicinal Chemistry. 19:6557-6562.   10.1016/j.bmc.2011.06.053   AbstractWebsite

Three new depsipeptides, fijimycins A-C (1-3), together with the known etamycin A (4), were isolated and identified from the fermentation broth of strain CNS-575, a Streptomyces sp. cultured from a marine sediment sample collected off Nasese, Fiji. The planar structures of the new fijimycins were assigned by combined interpretation of NMR and MS/MS spectroscopic data. These assignments were complicated by the fact that 1-3 occurred as complex amide conformational mixtures. The absolute configurations of the component amino acids were established using the Marfey's method. Fijimycins A-C, and etamycin A, were shown to possess significant in vitro antibacterial activity against three methicillin-resistant Staphylococcus aureus (MRSA) strains with MIC(100) values between 4 and 16 mu g mL(-1). (C) 2011 Elsevier Ltd. All rights reserved.