research highlights

TRANSLATION peptide bond cause rebinding of EF-Tu with the aromatic ring without compromising Tick tock aa-tRNA already residing within the A site. enantioselectivity. The incorporation of PNAS 117, 3610–3620 (2020) The phenomenon could also be observed reactive handles such as halogens or alkyne in normal translation processes, but at a groups on the aromatic ring thus provided much lower frequency. Rebinding of EF-Tu the capability for further functionalization increased the rate of GTP hydrolysis for each and diversification beyond the tolerance of peptide-bond formation event, suggesting that the CALB enzyme. This chemoenzymatic EF-Tu promotes translation at the expense of approach to macrocycle synthesis provides energy consumption. This study reflects the a more environmentally friendly and advantage of smFRET and MD simulation stereoselective route to potentially useful new methods in studying complex systems with compounds. CD multiple components and gaining molecular insights into timing in translational events. YS https://doi.org/10.1038/s41589-020-0512-2

https://doi.org/10.1038/s41589-020-0515-z ANTIBIOTIC DISCOVERY BIOCATALYSIS A tell-tale absence Credit: PNAS Locked on target Nature 578, 582–587 (2020) Science 367, 917–921 (2020) Translation is finely regulated in a highly OH H O N ordered manner to ensure the correct Planar chirality, resulting from a lack of OH O H O H transfer of genetic information into proteins. symmetry with respect to a plane, can arise O N N O N N N H O Elongation factor Tu (EF-Tu) plays important when substituents on a macrocycle are locked H HN H O H O H N HO2C N N H roles in aminoacyl-tRNA (aa-tRNA) and unable to rotate. Such conformations O O O OH selection by forming a ternary complex can be critical for the biological activity HO HO OH OH HO with aa-tRNA and GTP and guiding its of a compound but are difficult to control OH Corbomycin entry into the ribosome. To investigate the during synthesis. As enzymes are often kinetics of EF-Tu in the translation process, naturally stereoselective, Gagnon et al. Credit: Nature Morse et al. used three-color smFRET turned to biocatalysis as an approach for imaging to simultaneously tag EF-Tu, making planar chiral macrocycles. Using the Natural product gene clusters often aa-tRNA and the ribosome in conjunction serine hydrolase Candida antarctica lipase encode resistance genes to protect the with molecular dynamics (MD) simulation, B (CALB), the authors demonstrated the producing organism against its own finding that EF-Tu dissociation from the ability to make macrocyclic paracyclophane bioactive compound, and these can ribosome occurs after GTP hydrolysis and rings of various sizes from aromatic diols and also hint at the product’s mechanism initiation of aa-tRNA fitting into the A diacid aliphatic linkers. The reaction was also of action. Focusing on these resistance site and prior to peptide-bond formation. amenable both to certain alternative linkers determinants in glycopeptide antibiotic Interestingly, inhibitors that block aa-tRNA containing a rigid diyne moiety or a disulfide (GPA) biosynthetic gene clusters, Culp et al. accommodation or slow formation of the bridge and to additional substituents on used clusters lacking known GPA resistance genes as a guide to find compounds with potentially novel mechanisms of action. MICROBIOME–HOST INTERACTIONS Two compounds encoded by such clusters, A gut reaction Nature 579, 123–129 (2020) complestatin and corbomycin, exhibited activity against vancomycin-resistant The composition of the microbiota of all metazoans plays an important role in Gram-positive bacteria, unlike typical host physiology, with microbe-derived natural products acting as the chemical GPAs. By examining their effects on various messengers interacting with host systems. To examine the global impact of the steps of peptidoglycan metabolism and microbiome on chemical composition, Quinn et al. performed metabolomics analyses genome sequencing of resistant mutants, across 96 sample sites, representing 29 different organs in both germ-free (GF) the authors identified the peptidoglycan- and colonized (SPF) mice, and found that the microbiome affects the chemical remodeling autolysin enzymes as the target make-up and metabolic transformations in all organs, including organs that are very for both complestatin and corbomycin. distant from the gastrointestinal (GI) tract. The most molecularly diverse region Both compounds inhibit a range of was the colon of SPF mice. An analysis of chemical transformations in metabolites in autolysins through directly binding to their the lower GI tract showed that the microbiota contributed more to catabolic breakdown peptidoglycan substrate and were effective as than to anabolism. However, among the signals associated with SPF mice that did topical antibacterials in a mouse MRSA skin contribute to anabolism were three unique amino acid amide conjugates of cholic infection model. These GPAs demonstrate acid that correlated with the presence of Clostridium sp. Two of these could agonize the utility of focusing on genetic resistance a key human bile acid receptor, FXR, and were also found, using data from public determinants for antibiotic discovery metabolomics repositories, to be linked to diet in animals and human gut dysbiosis and through genome mining. CD disease. These findings aid in understanding the connections between the microbiota, https://doi.org/10.1038/s41589-020-0513-1 metabolites, and host health. MB Mirella Bucci, Caitlin Deane and https://doi.org/10.1038/s41589-020-0514-0 Yiyun Song

Nature Chemical Biology | VOL 16 | April 2020 | 363 | www.nature.com/naturechemicalbiology 363