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Previous chemical investigation of the Irish deep-sea soft coral Duva florida led to the identification of tuaimenal A (10), a new merosesquiterpene containing a highly substituted chromene core and modest cytotoxicity against cervical cancer. Further MS/MS and NMR-guided investigation of this octocoral has resulted in the isolation and characterization of seven additional tuaimenal analogs, B-H (1-7), as well as two known A-ring aromatized steroids (8, 9), and additional tuaimenal A (10). Tuaimenals B, F, and G (1, 5, 6), bearing an oxygen at the C5 position, as well as monocyclic tuaimenal H (7), show increased cervical cancer inhibition profiles in comparison to that of 10. Tuaimenal G further displayed potent, selective cytotoxicity with an EC50 value of 0.04 μM against the C33A cell line compared to the CaSki cell line (EC50 20 μM). These data reveal the anticancer properties of tuaimenal analogs and suggest unique antiproliferation mechanisms across these secondary metabolites.

The pairing of analytical chemistry with genomic techniques represents a new wave in natural product chemistry. With an increase in the availability of sequencing and assembly of microbial genomes, interrogation into the biosynthetic capability of producers with valuable secondary metabolites is possible. However, without the development of robust, accessible, and medium to high throughput tools, the bottleneck in pairing metabolic potential and compound isolation will continue. Several innovative approaches have proven useful in the nascent stages of microbial genome-informed drug discovery. Here, we consider a number of these approaches which have led to prioritization of strain targets and have mitigated rediscovery rates. Likewise, we discuss integration of principles of comparative evolutionary studies and retrobiosynthetic predictions to better understand biosynthetic mechanistic details and link genome sequence to structure. Lastly, we discuss advances in engineering, chemistry, and molecular networking and other computational approaches that are accelerating progress in the field of omic-informed natural product drug discovery. Together, these strategies enhance the synergy between cutting edge omics, chemical characterization, and computational technologies that pitch the discovery of natural products with pharmaceutical and other potential applications to the crest of the wave where progress is ripe for rapid advances.

Cold water benthic environments are a prolific source of structurally diverse molecules with a range of bioactivities against human disease. Specimens of a previously chemically unexplored soft coral, Duva florida, were collected during a deep-sea cruise that sampled marine invertebrates along the Irish continental margin in 2018. Tuaimenal A (1), a cyclized merosesquiterpenoid representing a new carbon scaffold with a highly substituted chromene core, was discovered through exploration of the soft coral secondary metabolome via NMR-guided fractionation. The absolute configuration was determined through vibrational circular dichroism. Functional biochemical assays and in silico docking experiments found tuaimenal A selectively inhibits the viral main protease (3CLpro) of SARS-CoV-2.

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 nonribosomal 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 multimodular enzymatic machinery (hybrid type I-trans-AT polyketide synthase-nonribosomal 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 to 0.99). Through repeated rounds of metagenome sequencing followed by binning contigs into metagenome-assembled genomes, we were able to retrieve a nearly 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. IMPORTANCE Palmerolide 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. Synoicihabitans palmerolidicus 4.29-Mb genome encodes a repertoire of carbohydrate-utilizing and transport pathways, a chemotaxis system, flagellar biosynthetic capacity, and other regulatory elements enabling its ascidian-associated lifestyle. The palmerolide producer's genome also contains five distinct copies of the large palmerolide biosynthetic gene cluster that may provide structural complexity of palmerolide variants.

We previously discovered that one specific scalemic preparation of myricanol (1), a constituent of Myrica cerifera (bayberry/southern wax myrtle) root bark, could lower the levels of the microtubule-associated protein tau (MAPT). The significance is that tau accumulates in a number of neurodegenerative diseases, the most common being Alzheimer's disease (AD). Herein, a new synthetic route to prepare myricanol using a suitable boronic acid pinacol ester intermediate is reported. An X-ray crystal structure of the isolated myricanol (1) was obtained and showed a co-crystal consisting of (+)-aR,11S-myricanol (2) and (-)-aS,11R-myricanol (3) coformers. Surprisingly, 3, obtained from chiral separation from 1, reduced tau levels in both cultured cells and ex vivo brain slices from a mouse model of tauopathy at reasonable mid-to-low micromolar potency, whereas 2 did not. SILAC proteomics and cell assays revealed that 3 promoted tau degradation through an autophagic mechanism, which was in contrast to that of other tau-lowering compounds previously identified by our group. During the course of structure-activity relationship (SAR) development, we prepared compound 13 by acid-catalyzed dehydration of 1. 13 had undergone an unexpected structural rearrangement through the isomyricanol substitution pattern (e.g., 16), as verified by X-ray structural analysis. Compound 13 displayed robust tau-lowering activity, and, importantly, its enantiomers reduced tau levels similarly. Therefore, the semisynthetic analogue 13 provides a foundation for further development as a tau-lowering agent without its SAR being based on chirality.

As mean global temperatures continue to rise, regional seawater temperature measurements have revealed that some geographic areas are warming faster than others. One region that is experiencing particularly rapid warming is the western Antarctic Peninsula. Previous studies investigating direct effects of warming on Antarctic marine invertebrates have established that small increases in temperature can have significant impacts on aspects of behavior, physiology, and growth rates in these largely stenothermal organisms. To investigate how warming may impact feeding preferences of an ecologically important mesograzer on macroalgae of the Antarctic Peninsula, we examined the impacts of exposure to acute elevated temperature on the ecologically important omnivorous amphipod Gondogeneiea antarctica (Chevreux) at Palmer Station, Antarctica (64°46/S, 64°03/W) in April-May 2011. Amphipods were exposed to 1.5°C (mean monthly upper summer temperature) or 3.5°C (representative of current transient summer temperature peaks and projected mean for 2100) for a 24 h period. These amphipods were then used in choice-feeding assays with artificial food containing chemical extracts from six species of sympatric macroalgae known to produce feeding deterrents. We found that during acute exposure to elevated temperature (+2.0°C), amphipods lost their feeding preferences in assays with artificial foods containing lipophilic (one macroalga), hydrophilic (three macroalgae), or combined lipophilic/hydrophilic (one macroalga) extracts. Our findings suggest that increased frequency in transient peaks and longer-term upward trends in ambient summer seawater temperature have the potential to alter feeding preferences in a common mesograzer that could influence macroalgal communities that dominate benthic communities along the western Antarctic Peninsula., Introduction The rapid warming and concomitant reductions in the extent and duration of the annual sea ice (Martinson et al. 2008) make studies of marine organismal response to warming along [...]