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As Nature Chemical Biology approaches its third decade we asked a collection of chemical biologists, “What do you think are the most exciting frontiers or the most needed developments in your main field of research?” — here is what they said.

Eggerthella lenta is a prominent human gut bacterium implicated in several physiological processes, but its study has remained limited. Here, by developing a genetic toolbox for E. lenta, the authors provide insights into how the bacterium regulates drug and dietary compound metabolism.

The bacterial genotoxin colibactin induces DNA interstrand cross-links which pose a barrier to DNA replication. Here, the authors use Xenopus egg extracts to show that the Fanconi anemia pathway is responsible for repairing these cross-links.

Cylindrocyclophane biosynthesis involves an unexpected halogenated intermediate arising from chlorination of an unactivated carbon center by a halogenase, followed by dimerization through stereospecific enzymatic alkylation of resorcinol aromatic rings.

Post-translational modifications (PTMs) are important for the stability and function of many therapeutic proteins. Here, the authors develop a high-throughput workflow combining cell-free gene expression with AlphaLISA to rapidly characterize and engineer PTMs on both proteins and peptides.

Natural products discovery remains an ongoing challenge. Now, halide depletion offers a complementary approach to discover natural products whose biosynthesis requires halides, including products of cryptic halogenation. Halide depletion reveals that nostochlorosides, the products of an orphan biosynthetic gene cluster in Nostoc punctiforme, are polymerized by a halide-displacing etherifying enzyme.

Potent microbial toxins found in shellfish are possible starting points for drug discovery, but analogues are needed for biological testing. Toxin-modification enzymes now suggest a new approach for producing these analogues.

The gene cluster that produces the sponge-derived cytotoxin calyculin A has been located in an uncultivated bacterial symbiont. Biochemical analyses reveal a pyrophosphorylated protoxin as the true biosynthetic product and suggest that calyculins result from activated chemical defense.

The bacterial genotoxin colibactin triggers prophage-mediated lysis of neighbouring bacteria, a finding that provides insight into the dynamics of microbial communities and relationships between bacterial metabolite production and phage behaviour.

Biochemical characterization of glycogen-degrading enzymes in vaginal bacteria reveals that the vaginal microbiota possesses the ability to metabolize glycogen in this environment.

A substrate-guided design strategy generated highly potent inhibitors of the biosynthesis of the genotoxin colibactin by human gut bacteria. These inhibitors also enable a generalizable approach for chemically guided natural product discovery.

A novel multi-omics workflow, combining gut microbiome metagenomics, metatranscriptomics and metabolomics, enabled the identification of the microbial pathways responsible for the degradation of the immunomodulatory drug 5-ASA in the gut of patients with inflammatory bowel disease.

Phospholipase Ds (PLDs) transform phosphatidylcholine to choline, which can then be converted to disease-associated trimethylamine. Here, PLDs are identified in gut bacteria that support growth of other bacteria and are potential therapeutic targets.

The α-diazoester azaserine can be produced by Streptomyces albus engineered with a biosynthetic gene cluster and act as the carbene precursor for coupling with intracellularly produced styrene to generate unnatural amino acids containing a cyclopropyl group.

The biosynthetic pathway that produces the structurally uncharacterized gut bacterial genotoxin colibactin can produce unstable, macrocyclic products; however, the extent to which these structures contribute to colibactin’s biological activities is not yet fully understood. Now, two recent studies have provided new insights and reached distinct conclusions regarding their potential mechanisms of action and relevance for genotoxicity.

The natural products fosfazinomycin A and kinamycin D are structurally distinct except for a nitrogen-nitrogen (N-N) bond. Here, the authors show that fosfazinomycin and kinamycin share a common pathway for N-N bond formation that is different from pathways found for other natural products.

Germ-free mice were colonized with complex defined communities to show T cell recognition of commensals is focused on widely conserved, highly expressed cell-surface antigens, opening the door to new therapeutic strategies.

l-cysteine is required for the growth of Lactobacillus iners, a vaginal microbiome species typically associated with adverse outcomes that lacks cysteine biosynthesis pathways and key uptake mechanisms present in other lactobacilli. Cystine uptake inhibitors can be used to suppress L. iners abundance in vitro in favour of L. crispatus, a species associated with favourable outcomes.

Structure and mutagenesis of the colibactin-activating peptidase ClbP reveals a dimer with a substrate-binding transmembrane domain and a conserved polar network in its periplasmic domain that enforces selectivity for d-asparagine prodrug motifs.

Three distinct families of gut bacteria encode an unprecedented number of respiratory-like reductases per genome to perform anaerobic respiration of biomedically relevant substrates.

The metalloenzyme SznF catalyses the formation of an N–N bond in the biosynthesis of streptozotocin, providing insights into the enzymatic assembly of an N-nitroso group.

A nonribosomal peptide synthetase involved in colibactin biosynthesis utilizes S-adenosylmethionine as a nonproteinogenic amino acid building block, which is then converted into the cyclopropane moiety that is critical for colibactin's genotoxic activity.

Small-molecule inhibitors offer many advantages for manipulating the gut microbiome, both as tool compounds and as potential therapeutics. This Review highlights recent examples of inhibitors that target gut bacterial enzymatic activity as well as the challenges and opportunities associated with their design and development.

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.

A consortium of four human gut microbiota species, including Eggerthella lenta, can convert plant-derived lignans into bioactive enterolignans via a five-step pathway, providing mechanistic insight into the production of these protective metabolites.