Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product <scp>ET</scp>‐743

Schofield, Michael M.; Jain, Sunit; Porat, Daphne; Dick, Gregory J.; Sherman, David H.

doi:10.1111/1462-2920.12908

Cited by 91 publications

(81 citation statements)

References 57 publications

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“…"Candidatus Endobugula sertula" has, to our knowledge, never been cultured in the laboratory, and it has been previously suggested that its genome might be reduced (7), similar to some long-term symbionts of insects (15,18) and marine tunicates (14,16). Although the "Ca.…”

Section: Photorhabdus/ Xenorhabdusmentioning

confidence: 99%

“…Portions of the bry pathway for the bryostatins were recovered previously using clone library methods (6), but the complete genome sequence, including missing pieces of the bry pathway, has remained elusive due to recalcitrance of the symbiont to culture. A number of factors are thought to contribute to this recalcitrance, including the possibility of substantial genome reduction (7), which has been reported in other invertebrate symbioses (14)(15)(16). Indeed, the divergence of symbionts in genetically isolated hosts (17), as well as restriction to B. neritina and allied species, the vertical mode of symbiont transmission, and the ongoing inability to isolate and culture "Ca.…”

mentioning

confidence: 99%

“…Endobugula sertula" in order to determine whether the symbiosis has evolved to a state of codependency, evidenced by bacterial genome degradation, as in some other defensive symbioses (14)(15)(16). Shotgun DNA and RNA sequencing revealed a genome with few signs of reduction, largely intact mainstream metabolic pathways, and a putative mechanism of vertical transmission of "Ca.…”

mentioning

confidence: 99%

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Lack of Overt Genome Reduction in the Bryostatin-Producing Bryozoan Symbiont “Candidatus Endobugula sertula”

Miller

Vanee

Fong

et al. 2016

Appl Environ Microbiol

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The uncultured bacterial symbiont "Candidatus Endobugula sertula" is known to produce cytotoxic compounds called bryostatins, which protect the larvae of its host, Bugula neritina. The symbiont has never been successfully cultured, and it was thought that its genome might be significantly reduced. Here, we took a shotgun metagenomics and metatranscriptomics approach to assemble and characterize the genome of "Ca. Endobugula sertula." We found that it had specific metabolic deficiencies in the biosynthesis of certain amino acids but few other signs of genome degradation, such as small size, abundant pseudogenes, and low coding density. We also identified homologs to genes associated with insect pathogenesis in other gammaproteobacteria, and these genes may be involved in host-symbiont interactions and vertical transmission. Metatranscriptomics revealed that these genes were highly expressed in a reproductive host, along with bry genes for the biosynthesis of bryostatins. We identified two new putative bry genes fragmented from the main bry operon, accounting for previously missing enzymatic functions in the pathway. We also determined that a gene previously assigned to the pathway, bryS, is not expressed in reproductive tissue, suggesting that it is not involved in the production of bryostatins. Our findings suggest that "Ca. Endobugula sertula" may be able to live outside the host if its metabolic deficiencies are alleviated by medium components, which is consistent with recent findings that it may be possible for "Ca. Endobugula sertula" to be transmitted horizontally. IMPORTANCEThe bryostatins are potent protein kinase C activators that have been evaluated in clinical trials for a number of indications, including cancer and Alzheimer's disease. There is, therefore, considerable interest in securing a renewable supply of these compounds, which is currently only possible through aquaculture of Bugula neritina and total chemical synthesis. However, these approaches are labor-intensive and low-yielding and thus preclude the use of bryostatins as a viable therapeutic agent. Our genome assembly and transcriptome analysis for "Ca. Endobugula sertula" shed light on the metabolism of this symbiont, potentially aiding isolation and culturing efforts. Our identification of additional bry genes may also facilitate efforts to express the complete pathway heterologously. Marine invertebrates, such as tunicates and sponges, are known to harbor symbiotic communities of bacteria. Because these animals are sessile and have limited physical defenses, their microbiomes are thought to serve defensive functions, and bacterial symbionts in these invertebrates have been implicated in the production of many bioactive small molecules (1, 2). Such small molecules can possess therapeutically relevant activities, so there is great interest in studying the biosynthetic potential and symbiotic functions of these defensive microorganisms (1, 2). However, most symbionts (and most environmental bacteria in general [1,3,4]) are difficul...

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Section: Photorhabdus/ Xenorhabdusmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Lack of Overt Genome Reduction in the Bryostatin-Producing Bryozoan Symbiont “Candidatus Endobugula sertula”

Miller

Vanee

Fong

et al. 2016

Appl Environ Microbiol

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“…Microbial symbionts are thought to be the main source of bioactive natural products occurring in ascidians (Schmidt & Donia, 2010;Schofield et al, 2015), contributing both to the defensive mechanism of the sessile ascidian and to the metabolic needs of its host (Martínez-García et al, 2008;Erwin et al, 2014;Tianero et al, 2015). Assessing the ascidian holobiont's microbial communities, which may also be involved in the process of occupying new niches, is expected to shed new light on the processes that enable the colonization of new habitats by this species.…”

Section: Styela Plicatamentioning

confidence: 99%

Rapid establishment of the non-indigenous ascidian Styela plicata and its associated bacteria in marinas and fishing harbors along the Mediterranean coast of Israel

et al. 2017

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Styela plicata (Lesueur, 1823) (Tunicata; Stolidobranchia; Styelidae) is a solitary ascidian with a global distribution. Until recently it had not been observed along the Mediterranean coast of Israel, but is now to be found in many harbors attached to suspended ropes and other artificial structures. In order to monitor the populations of S. plicata, we surveyed eight harbors along the Israeli Mediterranean coast. Our results show that the condition and maintenance of each harbor significantly affected the presence of S. plicata. We also characterized the microbial communities in the tunic of three individuals using 16S rRNA gene tag pyrosequencing and compared them to those in the surrounding seawater, in order to determine whether the symbiotic bacteria may contribute to the successful establishment of this ascidian species. We found 15 bacterial phyla in total, of which 14 were present in the animal hosts: 6 were present in all of the individuals and 4 in two of the individuals. Three of the 15 phyla observed were absent in the surrounding seawater. The high variability among the three hosts suggests a mechanism of horizontal transmission and may play a role in the process of invading new and less tolerant niches.

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“…1 For example, bryostatins and ecteinascidins are produced in low abundance within marine animals, yet are used in clinical application despite incredible supply and development hurdles. 2,3 …”

Section: Introductionmentioning

confidence: 99%

Accessing chemical diversity from the uncultivated symbionts of small marine animals

et al. 2018

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Chemistry drives many biological interactions between the microbiota and host animals, yet it is often challenging to identify the chemicals involved. This poses a problem, as such small molecules are excellent sources of potential pharmaceuticals, pretested by nature for animal compatibility. We discovered anti-HIV compounds from small, marine tunicates from the Eastern Fields of Papua New Guinea. Tunicates are a reservoir for novel bioactive chemicals, yet their small size often impedes identification or even detection of the chemicals within. We solved this problem by combining chemistry, metagenomics, and synthetic biology to directly identify and synthesize the natural products. We show that these anti-HIV compounds, the divamides, are a novel family of lanthipeptides produced by symbiotic bacteria living in the tunicate. Neighboring animal colonies contain structurally related divamides that differ starkly in their biological properties, suggesting a role for biosynthetic plasticity in a native context where biological interactions take place.

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Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET‐743

Cited by 91 publications

References 57 publications

Lack of Overt Genome Reduction in the Bryostatin-Producing Bryozoan Symbiont “Candidatus Endobugula sertula”

Lack of Overt Genome Reduction in the Bryostatin-Producing Bryozoan Symbiont “Candidatus Endobugula sertula”

Rapid establishment of the non-indigenous ascidian Styela plicata and its associated bacteria in marinas and fishing harbors along the Mediterranean coast of Israel

Accessing chemical diversity from the uncultivated symbionts of small marine animals

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