Marcos Pires

Nature Microbiology, Published online: 07 October 2019; doi:10.1038/s41564-019-0568-5

Short-term exposure to a high-fat diet reduces colonization resistance to Salmonella Typhimurium infection in mice and is associated with increase bile salts and plasmid transfer; however, E. coli can provide a protective effect under these conditions.

A functional biosynthetic pathway formed from a combination of genes encoded by a bacterial endosymbiont and its insect host exhibits strong parallels to organelle evolution.

Nature, Published online: 02 October 2019; doi:10.1038/s41586-019-1589-1

A ‘click’ reaction is developed for the simple and rapid formation of azides from primary amines, and is used to prepare a library of over 1,200 azides for subsequent use in the existing triazole annulation click reaction.

Sactionine‐containing antibiotics (sactibiotics) are a growing class of peptide antibiotics belonging to the ribosomally synthesized and post‐translationally modified peptide (RiPP) superfamily. Here we report characterization of a novel sactibiotic thuricin Z from Bacillus thuringiensis. Unusually, biosynthesis of thuricin Z involves two radical S‐adenosylmethionine (SAM) enzymes ThzC and ThzD. Although ThzC and ThzD are highly divergent from each other, these two enzymes produced the same sactionine ring in the precursor peptide ThzA in vitro, and ThzC alone is able to produce the fully modified ThzA with 4 sactionine rings. Thuricin Z exhibits a narrow‐spectrum antibacterial activity against Bacillus cereus. A series of analysis, including confocal laser scanning microscopy, ultrathin sectioning transmission electron microscopy, scanning electron microscopy, and large unilamellar vesicles‐based fluorescence analysis, suggested that thuricin Z binds bacterial cell membrane and leads to membrane permeabilization.

Finding hidden bacteria: An AIEgen‐peptide‐based fluorescent bioprobe was designed as a phototheranostic agent for phagosome‐entrapped bacteria. Activation of the probe by caspase‐1 in infected macrophages leads to a fluorescent signal. Moreover, the AIEgen can serve as a photosensitizer for generation of reactive oxygen species, which induces highly efficient killing of the bacteria.

Abstract

The detection and elimination of intracellular bacteria remain a major challenge. In this work, we report an aggregation‐induced emission (AIE) bioprobe that can detect bacterial infection and kill bacteria surviving inside macrophages through a dynamic process, notably specific molecular tailoring of the probe by caspase‐1 activation in infected macrophages and accumulation of the residue on phagosomes containing bacteria, leading to light‐up fluorescent signals. Moreover, the AIEgen can serve as a photosensitizer for generation of reactive oxygen species (ROS); and the average ROS indicator fluorescent signal intensity per unit area in the bacterial phagosomes is approximately 2.7‐fold higher than that in the cytoplasm. This, in turn, induces bacteria killing with high efficiency and minimal cytotoxicity towards macrophages. We envision that this specific light‐up bioprobe may provide a new approach for selective and sensitive detection and eradication of intracellular bacterial infections.

Nature Microbiology, Published online: 30 September 2019; doi:10.1038/s41564-019-0569-4

Cooked and raw plant diets cause different changes in gut microbiome composition and function, including mechanisms of starch digestibility and xenobiotic availability, and consequently impact host energy status.

Defining specific protein interactions and spatially or temporally restricted local proteomes improves our understanding of all cellular processes, but obtaining such data is challenging, especially for rare proteins, cell types, or events. Proximity labeling enables discovery of protein neighborhoods defining functional complexes and/or organellar protein compositions. Recent technological improvements, namely two highly active biotin ligase variants (TurboID and miniTurbo), allowed us to address two challenging questions in plants: (1) what are in vivo partners of a low abundant key developmental transcription factor and (2) what is the nuclear proteome of a rare cell type? Proteins identified with FAMA-TurboID include known interactors of this stomatal transcription factor and novel proteins that could facilitate its activator and repressor functions. Directing TurboID to stomatal nuclei enabled purification of cell type- and subcellular compartment-specific proteins. Broad tests of TurboID and miniTurbo in Arabidopsis and N. benthamiana and versatile vectors enable customization by plant researchers.

Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of l-serine from glucose. Astrocytic l-serine was proposed to regulate NMDAR activity by shuttling to neurons to sustain d-serine production, but this hypothesis remains untested. We now report that inhibition of astrocytic Phgdh suppressed the de novo synthesis of...

Nature, Published online: 18 September 2019; doi:10.1038/s41586-019-1560-1

Delivery via caesarean section, maternal antibiotic prophylaxis and colonization by opportunistic pathogens associated with the hospital environment affect the composition of the gut microbiota of children from birth until infancy.

Nature Chemical Biology, Published online: 16 September 2019; doi:10.1038/s41589-019-0362-y

This Perspective summarizes recent discoveries that have laid the foundation for targeted degradation therapeutics and discusses the current state of understanding and consideration involved in developing these protein degraders.

A bacterial effector operates through a “betrayal-like” mechanism by masquerading as an HSP90 client as a means to achieve specificity for its target. This minimal kinase then phosphorylates a critical active site residue to inactivate an essential chaperone required for host innate immunity.

Nature Biotechnology, Published online: 09 September 2019; doi:10.1038/s41587-019-0241-9

Dereplication by inactivation of antibiotic production clusters in actinomycetes enables antibiotic discovery.

Nature Communications, Published online: 10 September 2019; doi:10.1038/s41467-019-11952-w

Complex traits associate with genetic variation and environment and their interaction. Here, the authors study the influence of different diets on trait variability in 1154 outbred mice from an advanced intercross line and find gene-diet interactions associated with spontaneous autoimmunity development in these animals.

Nature Chemical Biology, Published online: 09 September 2019; doi:10.1038/s41589-019-0356-9

The topology of homodimeric membrane protein EmrE is dynamic and includes unassisted flipping of an N-terminal helix in and out of the membrane long after co-translational insertion. Dimerization locks the helix to limit topological dynamics.

Tannerella forsythia is a Gram-negative oral pathogen. Together with Porphyromonas gingivalis and Treponema denticola it constitutes the “red complex” of bacteria, which is crucially associated with periodontitis...

Nature Medicine, Published online: 02 September 2019; doi:10.1038/s41591-019-0559-3

A comprehensive biobank of bacterial isolates with longitudinal and multi-omics characterization will advance understanding of the diversity and functions of human gut bacteria.

Looking at the effects of diet, microbiome, and host biology on drug responsiveness highlights pathways contributing to metformin’s effects on lifespan.

Small pseudopeptidic cages show enhanced chloride binding and transport across a lipid membrane at acidic pH. This increases their cytotoxicity towards lung adenocarcinoma cells in environments mimicking those surrounding solid tumors.

Abstract

Acidic microenvironments in solid tumors are a hallmark of cancer. Inspired by that, we designed a family of pseudopeptidic cage‐like anionophores displaying pH‐dependent activity. When protonated, they efficiently bind chloride anions. They also transport chloride through lipid bilayers, with their anionophoric properties improving at acidic pH, suggesting an H⁺/Cl⁻ symport mechanism. NMR studies in DPC micelles demonstrate that the cages bind chloride within the lipid phase. The chloride affinity and the chloride‐exchange rate with the aqueous bulk solution are improved when the pH is lowered. This increases cytotoxicity towards lung adenocarcinoma cells at the pH of the microenvironment of a solid tumor. These properties depend on the nature of the amino‐acid side chains of the cages, which modulate their lipophilicity and interactions with the cell membrane. This paves the way towards using pH as a parameter to control the selectivity of cytotoxic ionophores as anticancer drugs.

Hypervirulent Klebsiella pneumoniae (hvKp) is globally disseminating as a community-acquired pathogen causing life-threatening infections in healthy individuals. The fact that a dose as little as 50 bacteria is lethal to mice illustrates the dramatic increase of virulence associated with hvKp strains compared with classical K. pneumoniae (cKp) strains, which require...

ABSTRACT

O-antigens are glycopolymers in lipopolysaccharides expressed on the cell surface of Gram-negative bacteria. Variability in the O-antigen structure constitutes the basis for the establishment of the serotyping schema. We pursued a two-pronged approach to define the basis for O-antigen structural diversity. First, we developed a bottom-up systems biology approach to O-antigen metabolism by building a reconstruction of Salmonella O-antigen biosynthesis and used it to (i) update 410 existing Salmonella strain-specific metabolic models, (ii) predict a strain’s serogroup and its O-antigen glycan synthesis capability (yielding 98% agreement with experimental data), and (iii) extend our workflow to more than 1,400 Gram-negative strains. Second, we used a top-down pangenome analysis to elucidate the genetic basis for intraserogroup O-antigen structural variations. We assembled a database of O-antigen gene islands from over 11,000 sequenced Salmonella strains, revealing (i) that gene duplication, pseudogene formation, gene deletion, and bacteriophage insertion elements occur ubiquitously across serogroups; (ii) novel serotypes in the group O:4 B2 variant, as well as an additional genotype variant for group O:4, and (iii) two novel O-antigen gene islands in understudied subspecies. We thus comprehensively defined the genetic basis for O-antigen diversity.

IMPORTANCE Lipopolysaccharides are a major component of the outer membrane in Gram-negative bacteria. They are composed of a conserved lipid structure that is embedded in the outer leaflet of the outer membrane and a polysaccharide known as the O-antigen. O-antigens are highly variable in structure across strains of a species and are crucial to a bacterium’s interactions with its environment. They constitute the first line of defense against both the immune system and bacteriophage infections and have been shown to mediate antimicrobial resistance. The significance of our research is in identifying the metabolic and genetic differences within and across O-antigen groups in Salmonella strains. Our effort constitutes a first step toward characterizing the O-antigen metabolic network across Gram-negative organisms and a comprehensive overview of genetic variations in Salmonella.

Nature Cell Biology, Published online: 26 August 2019; doi:10.1038/s41556-019-0373-7

Kim et al. demonstrate neutrophil- and macrophage-enriched subtypes in triple-negative breast cancer and how these immune profiles affect therapeutic responses to immune checkpoint blockade.