Biology subjects

Murray, A. E.

Publications and source records attributed to Murray, A. E..

4 recordsLinked to original sources

bioRxiv2021

Discovery of an Antarctic ascidian-associated uncultivated Verrucomicrobia that encodes antimelanoma palmerolide biosynthetic capacity

The Antarctic marine ecosystem harbors a wealth of biological and chemical innovation that has risen in concert over millennia since the isolation of the continent and formation of the Antarctic circumpolar current. Scientific inquiry into the novelty of marine natural products produced by Antarctic benthic invertebrates led to the discovery of a bioactive macrolide, palmerolide A, that has specific activity against melanoma and holds considerable promise as an anticancer therapeutic. While this compound was isolated from the Antarctic ascidian Synoicum adareanum, its biosynthesis has since been hypothesized to be microbially mediated, given structural similarities to microbially-produced hybrid non-ribosomal peptide-polyketide macrolides. Here, we describe a metagenome-enabled investigation aimed at identifying the biosynthetic gene cluster (BGC) and palmerolide A-producing organism. A 74 Kbp candidate BGC encoding the multi-modular enzymatic machinery (hybrid Type I-trans-AT polyketide synthase-non-ribosomal peptide synthetase and tailoring functional domains) was identified and found to harbor key features predicted as necessary for palmerolide A biosynthesis. Surveys of ascidian microbiome samples targeting the candidate BGC revealed a high correlation between palmerolide-gene targets and a single 16S rRNA gene variant (R=0.83 - 0.99). Through repeated rounds of metagenome sequencing followed by binning contigs into metagenome-assembled genomes, we were able to retrieve a near-complete genome (10 contigs) of the BGC-producing organism, a novel verrucomicrobium within the Opitutaceae family that we propose here as Candidatus Synoicihabitans palmerolidicus. The refined genome assembly harbors five highly similar BGC copies, along with structural and functional features that shed light on the host-associated nature of this unique bacterium. ImportancePalmerolide A has potential as a chemotherapeutic agent to target melanoma. We interrogated the microbiome of the Antarctic ascidian, Synoicum adareanum, using a cultivation-independent high-throughput sequencing and bioinformatic strategy. The metagenome-encoded biosynthetic machinery predicted to produce palmerolide A was found to be associated with the genome of a member of the S. adareanum core microbiome. Phylogenomic analysis suggests the organism represents a new deeply-branching genus, Candidatus Synoicihabitans palmerolidicus, in the Opitutaceae family of the Verrucomicrobia phylum. The Ca. S. palmerolidicus 4.29 Mb genome encodes a repertoire of carbohydrate-utilizing and transport pathways enabling its ascidian-associated lifestyle. The palmerolide-producers genome also contains five distinct copies of the large palmerolide biosynthetic gene cluster that may provide structural complexity of palmerolide variants.

microbiology↗

bioRxiv2021

Palmerolide PKS-NRPS gene clusters characterized from the microbiome of an Antarctic ascidian

Complex interactions exist between microbiomes and their hosts. Increasingly, defensive metabolites that have been attributed to host biosynthetic capability are now being recognized as products of host-associated microbes. These unique metabolites often have bioactivity targets in human disease and can be purposed as pharmaceuticals. Polyketides are a complex family of natural products that often serve as defensive metabolites for competitive or pro-survival purposes for the producing organism, while demonstrating bioactivity in human diseases as cholesterol lowering agents, anti-infectives, and anti-tumor agents. Marine invertebrates and microbes are a rich source of polyketides. Palmerolide A, a polyketide isolated from the Antarctic ascidian Synoicum adareanum, is a vacuolar-ATPase inhibitor with potent bioactivity against melanoma cell lines. The biosynthetic gene clusters (BGCs) responsible for production of secondary metabolites are encoded in the genomes of the producers as discrete genomic elements. A candidate palmerolide BGC was identified from a S. adareanum microbiome-metagenome based on a high degree of congruence with a chemical structure-based retrobiosynthetic prediction. Protein family homology analysis, conserved domain searches, active site and motif identification were used to identify and propose the function of the [~]75 kb trans-acyltransferase (AT) polyketide synthase-non-ribosomal synthase (PKS-NRPS) domains responsible for the stepwise synthesis of palmerolide A. Though PKS systems often act in a predictable co-linear sequence, this BGC includes multiple trans-acting enzymatic domains, a non-canonical condensation termination domain, a bacterial luciferase-like monooxygenase (LLM), and is found in multiple copies within the metagenome-assembled genome (MAG). Detailed inspection of the five highly similar pal BGC copies suggests the potential for biosynthesis of other members of the palmerolide chemical family. This is the first delineation of a biosynthetic gene cluster from an Antarctic microbial species, recently proposed as Candidatus Synoicohabitans palmerolidicus. These findings have relevance for fundamental knowledge of PKS combinatorial biosynthesis and could enhance drug development efforts of palmerolide A through heterologous gene expression.

biochemistry↗

bioRxiv2020

Environmental vulnerability of the global ocean plankton community interactome

Marine plankton form complex communities of interacting organisms at the base of the food web, which sustain oceanic biogeochemical cycles, and help regulate climate. Though global surveys are starting to reveal ecological drivers underlying planktonic community structure, and predicted climate change responses, it is unclear how community-scale species interactions will be affected by climate change. Here we leveraged Tara Oceans sampling to infer a global ocean cross-domain plankton co-occurrence network - the community interactome - and used niche modeling to assess its vulnerabilities to environmental change. Globally, this revealed a plankton interactome self-organized latitudinally into marine biomes (Trades, Westerlies, Polar), and more connected poleward. Integrated niche modeling revealed biome-specific community interactome responses to environmental change, and forecasted most affected lineages for each community. These results provide baseline approaches to assess community structure and organismal interactions under climate scenarios, while identifying plausible plankton bioindicators for ocean monitoring of climate change.

ecology↗

bioRxiv2020

Dissecting the microbiome of a polyketide-producing ascidian across the Anvers Island archipelago, Antarctica

Polar marine ecosystems hold the potential for bioactive compound biodiscovery, based on their untapped macro- and microorganismal diversity. Characterization of polar benthic marine invertebrate-associated microbiomes is limited to few studies. This study was motivated by our interest in better understanding the microbiome structure and composition of the ascidian, Synoicum adareanum, in which the bioactive macrolide that has specific activity to melanoma, palmerolide A (PalA), was found. PalA bears structural resemblance to a combined nonribosomal peptide polyketide, that has similarities to microbially-produced macrolides. We conducted a spatial survey to assess both PalA levels and microbiome composition in S. adareanum in a region of the Antarctic Peninsula near Anvers Island (64{degrees} 46'S, 64{degrees} 03'W). PalA was ubiquitous and abundant across a collection of 21 ascidians (3 subsamples each) sampled from seven sites across the Anvers Island archipelago. The microbiome composition (V3-V4 16S rRNA gene sequence variants) of these 63 samples revealed a core suite of 21 bacteria, 20 of which were distinct from regional bacterioplankton. Co-occurrence analysis yielded several potentially interacting subsystems and, although the levels of PalA detected were not found to correlate with specific sequence variants, the core members appeared to occur in a preferred optimum and tolerance range of PalA levels. Taking these results together with an analysis of biosynthetic potential of related microbiome taxa indicates a core microbiome with substantial promise for natural product biosynthesis that likely interact with the host and with each other.

microbiology↗