Marcos Pires

Macrocycles, compounds containing a ring of 12 or more atoms, find use in human medicine, fragrances, and biological ion sensing. The efficient preparation of macrocycles is a fundamental challenge in synthetic organic chemistry because the high entropic cost of large-ring closure allows undesired intermolecular reactions to compete. Here, we present a bioinspired strategy for macrocycle formation through carbon–carbon bond formation. The process relies on a catalytic oligomer containing α- and β-amino acid residues to template the ring-closing process. The α/β-peptide foldamer adopts a helical conformation that displays a catalytic primary amine–secondary amine diad in a specific three-dimensional arrangement. This catalyst promotes aldol reactions that form rings containing 14 to 22 atoms. Utility is demonstrated in the synthesis of the natural product robustol.

Liu et al. show that symbiosis between host and commensal Staphylococcus epidermidis contributes to a shift in the nasal microbiome during adolescence in humans, with a decrease of opportunistic pathogens. S. epidermidis induces antimicrobial peptide production in nasal epithelia, killing competing pathogens, but is resistant to those peptides due to biofilm formation.

The gut microbiota produce hundreds of molecules that are present at high concentrations in the host circulation. Unraveling the contribution of each molecule to host biology remains difficult. We developed a system for constructing clean deletions in Clostridium spp., the source of many molecules from the gut microbiome. By applying this method to the model commensal organism Clostridium sporogenes, we knocked out genes for 10 C. sporogenes–derived molecules that accumulate in host tissues. In mice colonized by a C. sporogenes for which the production of branched short-chain fatty acids was knocked out, we discovered that these microbial products have immunoglobulin A–modulatory activity.

Bacteria have developed several evolutionary strategies to protect their cell membranes (CMs) from the attack of antibiotics and antimicrobial peptides (AMPs) produced by the innate immune system, including remodeling of phospholipid content and localization. Multidrug-resistant Enterococcus faecalis, an opportunistic human pathogen, evolves resistance to the lipopeptide daptomycin and AMPs by...

Nature Chemical Biology, Published online: 09 December 2019; doi:10.1038/s41589-019-0421-4

A hydrophobic tagging method is used to develop a selective degrader for the chromatin regulator EZH2, which inhibits proliferation of triple-negative breast cancer cell lines in vitro and in vivo.

Nature Communications, Published online: 06 December 2019; doi:10.1038/s41467-019-13336-6

Anti-inflammatory treatments for gastrointestinal diseases can often have detrimental side effects. Here the authors engineer E. coli Nissle 1917 to create a fibrous matrix that has a protective effect in DSS-induced colitis mice.

Nature, Published online: 05 December 2019; doi:10.1038/d41586-019-03725-8

Gut neurons that trigger unpleasant symptoms also rally the body’s defenses against Salmonella.

ABSTRACT

Lipoteichoic acid (LTA) is an abundant polymer of the Gram-positive bacterial cell envelope and is essential for many species. Whereas the exact function of LTA has not been elucidated, loss of LTA in some species affects hydrophobicity, biofilm formation, and cell division. Using a viable LTA-deficient strain of the human oral commensal Streptococcus gordonii, we demonstrated that LTA plays an important role in surface protein presentation. Cell wall fractions derived from the wild-type and LTA-deficient strains of S. gordonii were analyzed using label-free mass spectroscopy. Comparisons showed that the abundances of many proteins differed, including (i) SspA, SspB, and S. gordonii 0707 (SGO_0707) (biofilm formation); (ii) FtsE (cell division); (iii) Pbp1a and Pbp2a (cell wall biosynthesis and remodeling); and (iv) DegP (envelope stress response). These changes in cell surface protein presentation appear to explain our observations of altered cell envelope homeostasis, biofilm formation, and adhesion to eukaryotic cells, without affecting binding and coaggregation with other bacterial species, and provide insight into the phenotypes revealed by the loss of LTA in other species of Gram-positive bacteria. We also characterized the chemical structure of the LTA expressed by S. gordonii. Similarly to Streptococcus suis, S. gordonii produced a complex type I LTA, decorated with multiple d-alanylations and glycosylations. Hence, the S. gordonii LTA appears to orchestrate expression and presentation of cell surface-associated proteins and functions.

IMPORTANCE Discovered over a half-century ago, lipoteichoic acid (LTA) is an abundant polymer found on the surface of Gram-positive bacteria. Although LTA is essential for the survival of many Gram-positive species, knowledge of how LTA contributes to bacterial physiology has remained elusive. Recently, LTA-deficient strains have been generated in some Gram-positive species, including the human oral commensal Streptococcus gordonii. The significance of our research is that we utilized an LTA-deficient strain of S. gordonii to address why LTA is physiologically important to Gram-positive bacteria. We demonstrate that in S. gordonii, LTA plays an important role in the presentation of many cell surface-associated proteins, contributing to cell envelope homeostasis, cell-to-cell interactions in biofilms, and adhesion to eukaryotic cells. These data may broadly reflect a physiological role of LTA in Gram-positive bacteria.

This study was designed to investigate whether household cockroaches harbor cephalosporin-resistant enterobacteria that share resistance determinants with human inhabitants. From February through July 2016, wh...

Nature, Published online: 04 December 2019; doi:10.1038/s41586-019-1805-z

Chimeric antigen receptor (CAR) T cells engineered to overexpress the canonical AP-1 transcription factor c-Jun are resistant to T cell exhaustion, and provide enhanced therapeutic benefit in mouse tumour models.

Alcohol is a widely consumed dietary component by patients with autoimmune neuroinflammatory diseases, but current evidence on the effects of alcohol in these conditions is confounding. Epidemiological studies suggest moderate consumption of alcohol may be protective in some autoimmune diseases; however, this correlation has not been directly investigated. Here, we...

Molecularly imprinted polymer nanoparticles (MIP‐NPs) block the N‐terminal region of cadherins, the principal site responsible for cell–cell adhesion. The MIP‐NPs mimic therapeutic antibodies employed in cancer treatment by disrupting cell–cell adhesion, as confirmed by the disintegration of three‐dimensional tumor spheroids of human cervical adenocarcinoma (HeLa) cells.

Abstract

One of the most promising strategies to treat cancer is the use of therapeutic antibodies that disrupt cell–cell adhesion mediated by dysregulated cadherins. The principal site where cell–cell adhesion occurs encompasses Trp2 found at the N‐terminal region of the protein. Herein, we employed the naturally exposed highly conserved peptide Asp1‐Trp2‐Val3‐Ile4‐Pro5‐Pro6‐Ile7, as epitope to prepare molecularly imprinted polymer nanoparticles (MIP‐NPs) to recognize cadherins. Since MIP‐NPs target the site responsible for adhesion, they were more potent than commercially available therapeutic antibodies for inhibiting cell–cell adhesion in cell aggregation assays, and for completely disrupting three‐dimensional tumor spheroids as well as inhibiting invasion of HeLa cells. These biocompatible supramolecular anti‐adhesives may potentially be used as immunotherapeutic or sensitizing agents to enhance antitumor effects of chemotherapy.

A real‐time in vivo imaging method to fulfill the unmet need for gut microbiota visualization was developed by integrating the strategy of d‐amino acid‐based metabolic labeling and NIR‐II fluorescence imaging. The versatility of this technique was demonstrated in imaging different bacterial species, and in the study of gastrointestinal motility‐induced gut microbiota biogeography changes.

Abstract

Deepening our understanding of mammalian gut microbiota has been greatly hampered by the lack of a facile, real‐time, and in vivo bacterial imaging method. To address this unmet need in microbial visualization, we herein report the development of a second near‐infrared (NIR‐II)‐based method for in vivo imaging of gut bacteria. Using d‐propargylglycine in gavage and then click reaction with an azide‐containing NIR‐II dye, gut microbiota of a donor mouse was strongly labeled with NIR‐II fluorescence on their peptidoglycan. The bacteria could be readily visualized in recipient mouse gut with high spatial resolution and deep tissue penetration under NIR irradiation. The NIR‐II‐based metabolic labeling strategy reported herein, provides, to the best of our knowledge, the first protocol for facile in vivo visualization of gut microbiota within deep tissues, and offers an instrumental tool for deciphering the complex biology of these gut “dark matters”.

Nature Biotechnology, Published online: 02 December 2019; doi:10.1038/s41587-019-0341-6

Engineering and manipulating phase-separated liquid organelles is the latest frontier in the quest to mimic and interrogate living systems at the molecular level.

Nature Chemical Biology, Published online: 02 December 2019; doi:10.1038/s41589-019-0412-5

3D printing agarose hydrogels embedded with Bacillus subtilis spores produce custom-shaped materials that are resistant to environmental stresses, while the bacteria maintain the ability to germinate on the surface and respond to stimuli.

Human population growth, soil degradation, and agrochemical misuse are significant challenges that agriculture must face in the upcoming decades as it pertains to global food production. Seed enhancement technologies will play a pivotal role in supporting food security by enabling germination of seeds in degraded environments, reducing seed germination time,...

Nature, Published online: 27 November 2019; doi:10.1038/s41586-019-1760-8

Individual cobalt phthalocyanine derivative molecules immobilized on carbon nanotubes effectively catalyse the electroreduction of CO2 to methanol via a domino process with high activity and selectivity and stable performance.

Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

A tip of the hap: A time‐resolved chemical proteomics strategy enables host and pathogen temporal interaction profiling (HAPTIP) for tracking the entry of bacteria into host cell.

Abstract

Studying the dynamic interaction between host cells and pathogen is vital but remains technically challenging. We describe herein a time‐resolved chemical proteomics strategy enabling host and pathogen temporal interaction profiling (HAPTIP) for tracking the entry of a pathogen into the host cell. A novel multifunctional chemical proteomics probe was introduced to label living bacteria followed by in vivo crosslinking of bacteria proteins to their interacting host‐cell proteins at different time points initiated by UV for label‐free quantitative proteomics analysis. We observed over 400 specific interacting proteins crosslinked with the probe during the formation of Salmonella‐containing vacuole (SCV). This novel chemical proteomics approach provides a temporal interaction profile of host and pathogen in high throughput and would facilitate better understanding of the infection process at the molecular level.

Responses of solid tumors to chimeric antigen receptor (CAR) T cell therapy are often minimal. This is potentially due to a lack of sustained activation and proliferation of CAR T cells when encountering antigen in a profoundly immunosuppressive tumor microenvironment. In this study, we investigate if inducing an interaction between...

The virus bacteriophage T4, from the family Myoviridae, employs an intriguing contractile injection machine to inject its genome into the bacterium Escherichia coli. Although the atomic structure of phage T4 is largely understood, the dynamics of its injection machinery remains unknown. This study contributes a system-level model describing the nonlinear...

Nature Chemical Biology, Published online: 25 November 2019; doi:10.1038/s41589-019-0404-5

Sulfur-triazole exchange (SuTEx) chemistry is a tunable platform for covalent chemoproteomic probes that selectively target tyrosines, used to identify residues with enhanced nucleophilicity and monitor activation of phosphotyrosine sites.

Nature Chemical Biology, Published online: 25 November 2019; doi:10.1038/s41589-019-0401-8

A potent inhibitor of the MRSA virulence regulator, GraR, reverses methicillin resistance, inhibits biofilm formation, limits bacterial survival in macrophages and attenuates virulence in vitro, synergizing with cationic antimicrobial peptides.

Nature, Published online: 20 November 2019; doi:10.1038/s41586-019-1791-1

A new antibiotic selectively kills Gram-negative pathogens

Léger et al. show that β-lactams treatment enhances superoxide and hydrogen peroxide production in Enterococcus faecalis in a mainly demethylmenaquinone (DMK)-dependent process. In the absence of respiration, the antibiotics trigger the accumulation of the reduced form of DMK, a respiratory chain component, which increases the adventitious reactivity with oxygen.

Nature, Published online: 18 November 2019; doi:10.1038/d41586-019-03495-3

Immunotherapy approaches seek to boost immune responses against cancer. A single antibody engineered to recognize three targets shows promise, when tested in animals, in improving the ability of T cells to target cancer.