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Publications

Griseorhodins D-F, Neuroactive Intermediates and End Products of Post-PKS Tailoring Modification in Griseorhodin Biosynthesis

Lin Z, Zachariah MM, Marett L, Hughen RW, Teichert RW, Concepcion GP, Haygood MG, Olivera BM, Light AR, Schmidt EW.view the article

Abstract: The griseorhodins belong to a family of extensively modified aromatic polyketides that exhibit activities such as inhibition of HIV reverse transcriptase and human telomerase. The vast structural diversity of this group of polyketides is largely introduced by enzymatic oxidations, which can significantly influence the bioactivity profile. Four new compounds, griseorhodins D-F, were isolated from a griseorhodin producer, Streptomyces sp. CN48+, based upon their enhancement of calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, griseorhodins D1 and D2, were shown to be identical to the major, previously uncharacterized products of a grhM mutant in an earlier griseorhodin biosynthesis study. Their structures enabled the establishment of a more complete hypothesis for the biosynthesis of griseorhodins and related compounds. The other two compounds, griseorhodins E and F, represent new products of post-polyketide synthase tailoring in griseorhodin biosynthesis and showed significant binding activity in a human dopamine active transporter assay.

Boronated tartrolon antibiotic produced by symbiotic cellulose-degrading bacteria in shipworm gills

Sherif I. Elshahawi, Amaro E. Trindade-Silva, Amro Hanora, Andrew W. Han, Malem S. Flores, Vinicius Vizzoni, Carlos G. Schrago, Carlos A. Soares, Gisela P. Concepcion, Dan L. Distel, Eric W. Schmidt, and Margo G. Haygood view the article

Abstract: Shipworms are marine wood-boring bivalve mollusks (family Teredinidae) that harbor a community of closely related Gammaproteobacteria as intracellular endosymbionts in their gills. These symbionts have been proposed to assist the shipworm host in cellulose digestion and have been shown to play a role in nitrogen fixation. The genome of one strain of Teredinibacter turnerae, the first shipworm symbiont to be cultivated, was sequenced, revealing potential as a rich source of polyketides and nonribosomal peptides. Bioassay-guided fractionation led to the isolation and identification of two macrodioloide polyketides belonging to the tartrolon class. Both compounds were found to possess antibacterial properties, and the major compound was found to inhibit other shipworm symbiont strains and various pathogenic bacteria. The gene cluster responsible for the synthesis of these compounds was identified and characterized, and the ketosynthase domains were analyzed phylogenetically. Reverse-transcription PCR in addition to liquid chromatography and high-resolution mass spectrometry and tandem mass spectrometry revealed the transcription of these genes and the presence of the compounds in the shipworm, suggesting that the gene cluster is expressed in vivo and that the compounds may fulfill a specific function for the shipworm host. This study reports tartrolon polyketides from a shipworm symbiont and unveils the biosynthetic gene cluster of a member of this class of compounds, which might reveal the mechanism by which these bioactive metabolites are biosynthesized.

Nobilamides A-H, long-acting transient receptor potential vanilloid-1 (TRPV1) antagonists from mollusk-associated bacteria

Lin Z, Reilly CA, Antemano R, Hughen RW, Marett L, Concepcion GP, Haygood MG, Olivera BM, Light A, Schmidt EW.  view the article

Abstract: New compounds nobilamides A-H and related known compounds A-3302-A and A-3302-B were isolated based upon their suppression of capsaicin-induced calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, nobilamide B and A-3302-A, were shown to be long-acting antagonists of mouse and human TRPV1 channels, abolishing activity for >1 h after removal of drug presumably via a covalent attachment. Other derivatives also inhibited the TRPV1 channel, albeit with low potency, affording a structure-activity profile to support the proposed mechanism of action. While the activities were modest, we propose a new mechanism of action and a new site of binding for these inhibitors that may spur development of related analogues for treatment of pain.

 

Microbial Distribution and Abundance in the Digestive System of Five Shipworm Species (Bivalvia: Teredinidae)

Meghan A. Betcher, Jennifer M. Fung, Andrew W. Han, Roberta O’Connor, Romell Seronay, Gisela P. Concepcion, Daniel L. Distel, Margo G. Haygood view the article

Abstract: Marine bivalves of the family Teredinidae (shipworms) are voracious consumers of wood in marine environments. In several shipworm species, dense communities of intracellular bacterial endosymbionts have been observed within specialized cells (bacteriocytes) of the gills (ctenidia). These bacteria are proposed to contribute to digestion of wood by the host. While the microbes of shipworm gills have been studied extensively in several species, the abundance and distribution of microbes in the digestive system have not been adequately addressed. Here we use Fluorescence In-Situ Hybridization (FISH) and laser scanning confocal microscopy with 16S rRNA directed oligonucleotide probes targeting all domains, domains Bacteria and Archaea, and other taxonomic groups to examine the digestive microbiota of 17 specimens from 5 shipworm species (Bankia setacea, Lyrodus pedicellatus, Lyrodus massa, Lyrodus sp. and Teredo aff. triangularis). These data reveal that the caecum, a large sac-like appendage of the stomach that typically contains large quantities of wood particles and is considered the primary site of wood digestion, harbors only very sparse microbial populations. However, a significant number of bacterial cells were observed in fecal pellets within the intestines. These results suggest that due to low abundance, bacteria in the caecum may contribute little to lignocellulose degradation. In contrast, the comparatively high population density of bacteria in the intestine suggests a possible role for intestinal bacteria in the degradation of lignocellulose.

Totopotensamides, polyketide-cyclic peptide hybrids from a mollusk-associated bacterium Streptomyces sp.

Lin Z, Flores M, Forteza I, Henriksen NM, Concepcion GP, Rosenberg G, Haygood MG, Olivera BM, Light AR, Cheatham TE 3rd, Schmidt EW. view the article

Abstract: Two new compounds, the peptide-polyketide glycoside totopotensamide A (1) and its aglycone totopotensamide B (2), were isolated from a Streptomyces sp. cultivated from the gastropod mollusk Lienardia totopotens collected in the Philippines. The compounds contain a previously undescribed polyketide component, a novel 2,3-diaminobutyric acid-containing macrolactam, and a new amino acid, 4-chloro-5,7-dihydroxy-6-methylphenylglycine. The application of Marfey's method to phenylglycine derivatives was explored using quantum mechanical calculations and NMR.
 
The complete genome of Teredinibacter turnerae T7901: an intracellular endosymbiont of marine wood-boring bivalves (family Teredinidae) 

Joyce C. Yang, A. Scott Durkin, Ramana Madupu, Nathan A. Ekborg, Bernard Henrissat, Sandra Schwartz, Joseph C. Mougous, Chandra S. Pedamallu, Lauren Fields, Amaro E. Trindade-Silva, Carlos A. G. Soares, Sherif Elshahawi, Amro Hanora, Margo G. Haygood, Janos Posfai, Jack Benner, Casey Swaim, John Nove, Brian Anton, Kshitiz Chaudhary, Jeremy Foster, Alex Holman, Sanjay Kumar, Philip A Lessard, Yvette A. Luyten, Barton Slatko, Nicole Wood, Bo Wu, John Zehr, Max Teplitski, Naomi Ward, Jonathan A. Eisen, Jonathan H. Badger, and Daniel L. Distel   view the article on PLoS One

Abstract: Here we report the complete genome sequence of Teredinibacter turnerae T7901. T. turnerae is a marine gamma proteobacterium that occurs as an intracellular endosymbiont in the gills of wood-boring marine bivalves of the family Teredinidae (shipworms). This species is the sole cultivated member of an endosymbiotic consortium thought to provide the host with enzymes, including cellulases and nitrogenase, critical for digestion of wood and supplementation of the host's nitrogen-deficient diet. T. turnerae is closely related to the free-living marine polysaccharide degrading bacterium Saccharophagus degradans str. 2-40 and to as yet uncultivated endosymbionts with which it coexists in shipworm cells. Like S. degradans, the T. turnerae genome encodes a large number of enzymes predicted to be involved in complex polysaccharide degradation (> 100). However, unlike S. degradans, which degrades a broad spectrum (>10 classes) of complex plant, fungal and algal polysaccharides, T. turnerae primarily encodes enzymes associated with deconstruction of terrestrial woody plant material. Also unlike S. degradans, T. turnerae dedicates a large proportion of its genome to genes predicted to function in secondary metabolism. Despite its intracellular niche, the T. turnerae genome lacks many features associated with obligate intracellular existence (e.g. reduced genome size, reduced %G+C, loss of genes of core metabolism) and displays evidence of adaptations common to free-living bacteria (e.g. defense against bacteriophage infection). Thus, the T. turnerae genome provides insights into the range of genomic adaptations associated with intracellular endosymbiosis as well as enzymatic mechanisms relevant to the recycling of plant materials in marine environments and the production of cellulose-derived biofuels.

 
A New Species of Lienardia (Gastropoda: Conoidea) from the Philippines and the Spratly Islands

Gary Rosenberg and Peter Stahlschmidt (Academy of Natural Sciences, 1900 Benjamin Franklin Parkway, Philadelphia, PAand Institute for Environmental Sciences, University of Koblenz-Landau,Germany)

Abstract: A new species of Lienardia (Conoidea: Clathurellidae) is described from the Philippines and Spratly Islands and compared to L. giliberti Souverbie, 1874, with which it has been confused. The species is routinely found in lumun-lumun nets in the southern Philippines, particularly in the Panglao area, in depths of 50 and HO m. Correlations between radular morphology and shell coloration support maintaining Lienardia and Clathurella as distinct genera.

 
Molecular phylogeny of Pholadoidea Lamarck, 1809 supports a single origin for xylotrophy (wood feeding) and xylotrophic bacterial endosymbiosis in Bivalvia.
Distel DL, Amin M, Burgoyne A, Linton E, Mamangkey G, Morrill W, Nove J, Wood N, Yang J.  view the article

Abstract: The ability to consume wood as food (xylotrophy) is unusual among animals. In terrestrial environments, termites and other xylotrophic insects are the principle wood consumers while in marine environments wood-boring bivalves fulfill this role. However, the evolutionary origin of wood feeding in bivalves has remained largely unexplored. Here we provide data indicating that xylotrophy has arisen just once in Bivalvia in a single wood-feeding bivalve lineage that subsequently diversified into distinct shallow- and deep-water branches, both of which have been broadly successful in colonizing the world's oceans. These data also suggest that the appearance of this remarkable life habit was approximately coincident with the acquisition of bacterial endosymbionts. Here we generate a robust phylogeny for xylotrophic bivalves and related species based on sequences of small and large subunit nuclear rRNA genes. We then trace the distribution among the modern taxa of morphological characters and character states associated with xylotrophy and xylotrepesis (wood-boring) and use a parsimony-based method to infer their ancestral states. Based on these ancestral state reconstructions we propose a set of plausible hypotheses describing the evolution of symbiotic xylotrophy in Bivalvia. Within this context, we reinterpret one of the most remarkable progressions in bivalve evolution, the transformation of the "typical" myoid body plan to create a unique lineage of worm-like, tube-forming, wood-feeding clams. The well-supported phylogeny presented here is inconsistent with most taxonomic treatments for xylotrophic bivalves, indicating that the bivalve family Pholadidae and the subfamilies Teredininae and Bankiinae of the family Teredinidae are non-monophyletic, and that the principle traits used for their taxonomic diagnosis are phylogenetically misleading.

Pulicatins A-E, neuroactive thiazoline metabolites from cone snail-associated bacteria

Lin Z, Antemano RR, Hughen RW, Tianero MD, Peraud O, Haygood MG, Concepcion GP, Olivera BM, Light A, Schmidt EW.  view the article

Abstract: The cone snail Conus pulicarius from the Philippines provides a specific habitat for actinomycetes and other bacteria. A phenotypic screen using primary cultures of mouse dorsal root ganglion neurons revealed that one C. pulicarius associate, Streptomyces sp. CP32, produces a series of natural products that enhance or diminish whole-cell Ca(2+) flux. These compounds include known thiazoline compounds and a series of new derivatives, pulicatins A-E (6-10). Individual compounds were shown to bind to a series of human receptors, with selective binding to the human serotonin 5-HT(2B) receptor. Here, we report the structure elucidation of the new compounds and results of the neurological assays.

Submitted

The microniche approach to discovering diverse actinomycete bacteria in cone snails 
Olivier Peraud, Jason S. Biggs, Ronald W. Hughen, Alan R. Light, Gisela P. Concepcion, Baldomero M. Olivera and Eric W. Schmidt

Abstract: Numerous studies have shown that actinomycetes can be symbionts in diverse organisms, including both plants and animals. Some actinomycetes benefit their host by producing small molecule secondary metabolites; the resulting symbioses are often developmentally complex. We examined the actinomycetes associated with three cone snails, venomous tropical marine gastropods which have been extensively examined because of their production of peptide-based neurological toxins but for which no microbiological studies have been reported. We used a microniche approach in which dissected tissue from each snail was treated as an individual sample in order to explore bacterial tissue specificity.Our results revealed a diverse, novel and highly culturable cone snail-associated actinomycete community suggesting that cone snails represent a rich source for discovering new actinomycete symbionts. Additionally, we found evidence that symbiotic actinomycetes are localized to specific cells within cone snails, which could be a possible result of co-evolution.

 

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