Summary Although biosynthetic gene clusters (BGCs) have been discovered for hundreds of bacterial metabolites, our knowledge of their diversity remains limited. Here, we used a novel algorithm to systematically identify BGCs in the extensive extant microbial sequencing data. Network analysis of the predicted BGCs revealed large gene cluster families, the vast majority uncharacterized. We experimentally characterized the most prominent family, consisting of two subfamilies of hundreds of BGCs distributed throughout the Proteobacteria; their products are aryl polyenes, lipids with an aryl head group conjugated to a polyene tail. We identified a distant relationship to a third subfamily of aryl polyene BGCs, and together the three subfamilies represent the largest known family of biosynthetic gene clusters, with more than 1,000 members. Although these clusters are widely divergent in sequence, their small molecule products are remarkably conserved, indicating for the first time the important roles these compounds play in Gram-negative cell biology.

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Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. Economically accessing the potential encoded within sequenced genomes promises to reinvigorate waning drug discovery pipelines and provide novel routes to intricate chemicals. This is a tremendous undertaking, as the pathways often comprise dozens of genes spanning as much as 100+ kiliobases of DNA, are controlled by complex regulatory networks, and the most interesting molecules are made by non-model organisms. Advances in synthetic biology address these issues, including DNA construction technologies, genetic parts for precision expression control, synthetic regulatory circuits, computer aided design, and multiplexed genome engineering. Collectively, these technologies are moving towards an era when chemicals can be accessed en mass based on sequence information alone. This will enable the harnessing of metagenomic data and massive strain banks for high-throughput molecular discovery and, ultimately, the ability to forward design pathways to complex chemicals not found in nature.

Identification of a new class of lanthionine synthetases provides insight into the mechanism and evolution of cyclic peptide biosynthesis.

Posttranslational modification of amino acids confers a range of structural features and activities on ribosomally synthesized peptides, many of which have potent antimicrobial or other biological activities. Cypemycin is an extensively modified linear peptide produced by Streptomyces sp. OH-4156 with potent in vitro activity against mouse leukemia cells. Cypemycin does not contain lanthionine bridges but exhibits some of the structural features of lantibiotics, notably dehydrated threonines (dehydrobutyrines) and a C-terminal S-[(Z)-2-aminovinyl]-D-cysteine. Consequently it was classified as a member of the lantibiotic family of posttranslationally modified peptides. Cypemycin also possesses two L-allo-isoleucine residues and an N-terminal N,N-dimethylalanine, both unique amino acid modifications. We identified and heterologously expressed the cypemycin biosynthetic gene cluster and performed a mutational analysis of each individual gene. We show that even the previously described modifications are carried out by unusual enzymes or via a modification pathway unrelated to lantibiotic biosynthesis. Bioinformatic analysis revealed the widespread occurrence of cypemycinlike gene clusters within the bacterial kingdom and in the Archaea. Cypemycin is the founding member of an unusual class of posttranslationally modified ribosomally synthesized peptides, the linaridins.Actinomycetes | antibiotic | enzymology | natural products | Streptomyces

Belkaid et al. show that Corynebacterium, a dominant skin microbe, promotes activation of γδ T cells in a mycolic acid–dependent manner without altering skin homeostasis. Such effect promotes inflammation in the context of high-fat-diet and psoriasis-like settings.

Sialic acid (Neu5Ac) is commonly found in terminal location of colonic mucins glycans where it is a much-coveted nutrient for gut bacteria including Ruminococcus gnavus. R. gnavus is part of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Synthetic cell therapy is a field that has broad potential for future applications in human disease treatment. Next generation therapies will consist of engineered bacterial strains capable of diagnosing disease, producing and delivering therapeutics, and controlling their numbers to meet containment and safety concerns. A thorough understanding of the microbial ecology of the human body and the interaction of the microbes with the immune system will benefit the choice of an appropriate chassis that engrafts stably and interacts productively with the resident community in specific body niches.