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A new manumycin-type natural product named pacificamide (1) and its candidate biosynthetic gene cluster (pac) were discovered from the marine actinobacterium Salinispora pacifica CNT-855. The structure of the compound was determined using NMR, electronic circular dichroism, and bioinformatic predictions. The pac gene cluster is unique to S. pacifica and found in only two of the 119 Salinispora genomes analyzed across nine species. Comparative analyses of biosynthetic gene clusters encoding the production of related manumycin-type compounds revealed genetic differences in accordance with the unique pacificamide structure. Further queries of manumycin-type gene clusters from public databases revealed their limited distribution across the phylum Actinobacteria and orphan diversity that suggests additional products remain to be discovered in this compound class. Production of the known metabolite triacsin D is also reported for the first time from the genus Salinispora. This study adds two classes of compounds to the natural product collective isolated from the genus Salinispora, which has proven to be a useful model for natural product research.

This study addresses the subject of Jonathan Edwards’s millennialism from his redemptive-historical vision. By situating him in the Reformation and post-Reformation contexts, taking into consideration his interaction with the intellectual challenges posed by the Enlightenment thinkers, it provides a more nuanced investigation of Edwards’s anticipation of the millennium. His millennialism is neither America-centric nor politically utopian. And he is not the one who originated or advocated the notion of the redeemer nation, as is frequently thought. His vision of the millennium is a Christ-reigning, Judeo-centric, and cosmic kingdom arriving on earth in a distant future. While some of his Protestant predecessors and Puritan contemporaries tended to centralize their own present times and nations, Edwards noticeably decentralized England and New England in terms of time, space, and people. This study sheds new light on the following issues. First, it extensively reviews Edwards’s millennial theology and provides another outlook on his continuity in and departures from the Reformed tradition. Second, it explores Edwards’s artful communication of his Christology in his millennialism. Third, this study highlights the Judeo-centric and cosmic nature as an innovative interpretive key to his millennialism, which provides a useful background to the current debates on Israel and the end times. Finally, this project ventures into two less well-known subjects—Israel and China in Edwards’s millennial vision—in order to revisit his conviction of Israel’s restoration to the Promised Land and his eschatological hope for China and the rest of heathen world.

While marine natural products have been investigated for anticancer drug discovery, they are barely screened against rare cancers. Thus, in our effort to discover potential drug leads against the rare cancer pseudomyxoma peritonei (PMP), which currently lacks effective drug treatments, we screened extracts of marine actinomycete bacteria against the PMP cell line ABX023-1. This effort led to the isolation of nine rearranged angucyclines from Streptomyces sp. CNZ-748, including five new analogues, namely, grincamycins P-T (1-5). The chemical structures of these compounds were unambiguously established based on spectroscopic and chemical analyses. Particularly, grincamycin R (3) possesses an S-containing α-l-methylthio-aculose residue, which was discovered in nature for the first time. All of the isolated compounds were evaluated against four PMP cell lines and some exhibited low micromolar inhibitory activities. To identify a candidate biosynthetic gene cluster (BGC) encoding the grincamycins, we sequenced the genome of the producing strain, Streptomyces sp. CNZ-748, and compared the BGCs detected with those linked to the production of angucyclines with different aglycon structures.

While specialized metabolites are thought to mediate ecological interactions, the evolutionary processes driving chemical diversification, particularly among closely related lineages, remain poorly understood. Here, we examine the evolutionary dynamics governing the distribution of natural product biosynthetic gene clusters (BGCs) among 118 strains representing all nine currently named species of the marine actinobacterial genus Salinispora. While much attention has been given to the role of horizontal gene transfer (HGT) in structuring BGC distributions, we find that vertical descent facilitates interspecies BGC diversification over evolutionary timescales. Moreover, we identified a distinct phylogenetic signal among Salinispora species at both the BGC and metabolite level, indicating that specialized metabolism represents a conserved phylogenetic trait. Using a combination of genomic analyses and liquid chromatography–high-resolution tandem mass spectrometry (LC-MS/MS) targeting nine experimentally characterized BGCs and their small molecule products, we identified gene gain/loss events, constrained interspecies recombination, and other evolutionary processes associated with vertical inheritance as major contributors to BGC diversification. These evolutionary dynamics had direct consequences for the compounds produced, as exemplified by species-level differences in salinosporamide production. Together, our results support the concept that specialized metabolites, and their cognate BGCs, can represent phylogenetically conserved functional traits with chemical diversification proceeding in species-specific patterns over evolutionary time frames. IMPORTANCE Microbial natural products are traditionally exploited for their pharmaceutical potential, yet our understanding of the evolutionary processes driving BGC evolution and compound diversification remain poorly developed. While HGT is recognized as an integral driver of BGC distributions, we find that the effects of vertical inheritance on BGC diversification had direct implications for species-level specialized metabolite production. As such, understanding the degree of genetic variation that corresponds to species delineations can enhance natural product discovery efforts. Resolving the evolutionary relationships between closely related strains and specialized metabolism can also facilitate our understanding of the ecological roles of small molecules in structuring the environmental distribution of microbes.

International audience; Genomics and metabolomics are widely used to explore specialized metabolite diversity. The Paired Omics Data Platform is a community initiative to systematically document links between metabolome and (meta)genome data, aiding identification of natural product biosynthetic origins and metabolite structures.

While specialized metabolites are thought to mediate ecological interactions, the evolutionary processes driving their diversification, particularly among closely related lineages, remain poorly understood. Here, we examine the evolutionary dynamics governing the distribution of natural product biosynthetic gene clusters (BGCs) using 118 strains within the marine actinomycete genus Salinispora. While previous evidence indicated that horizontal gene transfer (HGT) largely contributed to BGC diversity, we find that a majority of BGCs in Salinispora genomes are conserved through processes of vertical descent. In particular, vertical inheritance maintained BGCs over evolutionary timescales (millions of years) allowing for BGC diversification among Salinispora species. By coupling the genomic analyses with high-resolution tandem mass spectrometry (LC-MS/MS), we identified that BGC evolution in Salinispora proceeds largely through gene gain/loss events and constrained recombination that contributes to interspecies diversity at the gene, pathway, and metabolite levels. Consequently, the evolutionary processes driving BGC diversification had direct consequences for compound production and contributed to chemical diversification, as exemplified in our case study of the medically relevant proteosome inhibitors, the salinosporamides. Together, our results support the concept that specialized metabolites, and their cognate BGCs, represent functional traits associated with niche differentiation among Salinispora species. GRAPHICAL ABSTRACT SIGNIFICANCE Natural products are traditionally exploited for their pharmaceutical potential; yet what is often overlooked is that the evolution of the biosynthetic gene clusters (BGCs) encoding these small molecules likely affects the diversification of the produced compounds and implicitly has an impact on the compounds’ activities and ecological functions. And while the prevailing dogma in natural product research attributes frequent and widespread horizontal gene transfer (HGT) as an integral driver of BGC evolution, we find that the majority of BGC diversity derives from processes of vertical descent, with HGT events being rare. This understanding can facilitate informed biosynthetic predictions to identify novel natural products, in addition to uncovering how these specialized metabolites contribute to the environmental distribution of microbes.