With an ever-increasing amount of (meta)genomic data being deposited in sequence databases, (meta)genome mining for natural product biosynthetic pathways occupies a critical role in the discovery of novel pharmaceutical drugs, crop protection agents and biomaterials. The genes that encode these pathways are often organised into biosynthetic gene clusters (BGCs). In 2015, we defined the Minimum Information about a Biosynthetic Gene cluster (MIBiG): a standardised data format that describes the minimally required information to uniquely characterise a BGC. We simultaneously constructed an accompanying online database of BGCs, which has since been widely used by the community as a reference dataset for BGCs and was expanded to 2021 entries in 2019 (MIBiG 2.0). Here, we describe MIBiG 3.0, a database update comprising large-scale validation and re-annotation of existing entries and 661 new entries. Particular attention was paid to the annotation of compound structures and biological activities, as well as protein domain selectivities. Together, these new features keep the database up-to-date, and will provide new opportunities for the scientific community to use its freely available data, e.g. for the training of new machine learning models to predict sequence-structure-function relationships for diverse natural products. MIBiG 3.0 is accessible online at https://mibig.secondarymetabolites.org/.

We present results of a 2.5 yr survey of the rnacro~nfauna along the California coast north of Point Conception, between Purisima Point and Point San L u~s (USA), at outer-shelf and slope depths of 90 to 565 m. The study area, representing the southern offshore portion of the Santa Mdria Basin, IS a n oceanographically complex and productive region, which is also believed to contain major petroleum deposits. This area supports a highly diverse and abundant macroinfauna, represented mostly by crustaceans (34 %), polychaetes (31 "L), and molluscs (18 ' ' !L). Average numbers of species and densities (up to 151 0.lm-' and 28826 m-l, respectively. at water depths under 200 m) equal those reported for other productive regions, such a s Georges Bank and the North Sea. Spatial differences in the composition of these assemblages are related foremost to water depth in addition to variations in sedimentary and other depth-associated physical variables. Patterns of decreasing abundances and diversity with increasing depth appear to be due partly to a bottom dissolved-oxygen gradient (3.1 m1 1-' at 90 m to 0.6 m1 I-' at 565 m ) , which includes values at the low end that are below the oxygen tolerance of many b e n t h~c invertebrates. Variations in the percentage of sand explain further d~fferences that segregate some stations of comparable depth and oxygen Irvels. Macrofaunal variables also show significant temporal fluctuations, although distinct seasonal cycles are hard to detect and are not repeated throughout all sampling years and stations. The occurrence of density peaks in the sprlng durlng one or more sampling years at several of the stations, however, suggests a benthic response to upwelllng events. which are known to contribute to increases In new primary production and ultimately to increased energy supplies to the benthos. Results of thls study provide a basis for beg~nning to understand natural sources of variation in the benthos of the region, which should be considered in efforts to assess potential impacts of future oil development.

To tackle the growing problem of antibiotic resistance, it is essential to identify new bioactive compounds that are effective against resistant microbes and safe to use. Natural products and their derivatives are, and will continue to be, an important source of these molecules. Sea sponges harbour a diverse microbiome that co-exists with the sponge, and these bacterial communities produce a rich array of bioactive metabolites for protection and resource competition. For these reasons, the sponge microbiota constitutes a potential source of clinically relevant natural products. To date, efforts in bioprospecting for these compounds have focused predominantly on sponge specimens isolated from shallow water, with much still to be learned about samples from the deep sea. Here we report the isolation of a new Micromonospora strain, designated 28ISP2-46T, recovered from the microbiome of a mid-Atlantic deep-sea sponge. Whole-genome sequencing reveals the capacity of this bacterium to produce a diverse array of natural products, including kosinostatin and isoquinocycline B, which exhibit both antibiotic and antitumour properties. Both compounds were isolated from 28ISP2-46T fermentation broths and were found to be effective against a plethora of multidrug-resistant clinical isolates. This study suggests that the marine production of isoquinocyclines may be more widespread than previously supposed and demonstrates the value of targeting the deep-sea sponge microbiome as a source of novel microbial life with exploitable biosynthetic potential.

The deep ocean is the largest habitat for life on Earth, though the microorganisms that occupy this unique environmental niche remain largely unexplored. Due to the significant logistical and operational challenges associated with accessing the deep ocean, bioprospecting programmes that seek to generate novel products from marine organisms have, to date, focused predominantly on samples recovered from shallow seas. For this reason, the deep ocean remains a largely untapped resource of novel microbiological life and associated natural products. Here we report the establishment of the Bristol Sponge Microbiome Collection (BISECT), a unique repository of deep-sea microorganisms and associated metabolites isolated from the microbiota of marine sponges, recovered from previously unsurveyed regions of the mid Atlantic Ocean, at depths of 0.3–3 km. An integrated biodiscovery pipeline comprising molecular, genetic, bioinformatic and analytical tools is also described, which is being applied to interrogate this collection. The potential of this approach is illustrated using data reporting our initial efforts to identify antimicrobial natural product lead compounds. Prospects for the use of BISECT to address allied pharmaceutical needs, along with mechanisms of access to the collection are also discussed

Stereoselective carbon‐carbon bond forming reactions are quintessential transformations in organic synthesis. One example is the Diels‐Alder reaction, a [4+2] cycloaddition between a conjugated diene and a dienophile to form cyclohexenes. The development of biocatalysts for this reaction is paramount for unlocking sustainable routes to a plethora of important molecules. To obtain a comprehensive understanding of naturally evolved [4+2] cyclases, and to identify hitherto uncharacterised biocatalysts for this reaction, we constructed a library comprising forty‐five enzymes with reported or predicted [4+2] cycloaddition activity. Thirty‐one library members were successfully produced in recombinant form. In vitro assays employing a synthetic substrate incorporating a diene and a dienophile revealed broad‐ranging cycloaddition activity amongst these polypeptides. The hypothetical protein Cyc15 was found to catalyse an intramolecular cycloaddition to generate a novel spirotetronate. The crystal structure of this enzyme, along with docking studies, establishes the basis for stereoselectivity in Cyc15, as compared to other spirotetronate cyclases.