Marcos Pires

Nature Chemical Biology, Published online: 18 November 2019; doi:10.1038/s41589-019-0392-5

Microbiota-derived butyrate acylation of the key Salmonella enterica transcriptional regulator HilA attenuates virulence of the bacteria, blocking invasion of epithelial cells in vitro and dissemination in vivo.

Nature Biotechnology, Published online: 15 November 2019; doi:10.1038/d41587-019-00034-3

Pretomanid is the third new drug approved by the FDA in over 40 years, and a victory for the not-for-profit TB Alliance.

Caught in a trap: The antibiotic colistin targets lipopolysaccharide (LPS) in the Gram‐negative bacterial (GNB) membrane. This interaction is disrupted by free LPS released during infection (path a). A methylated gold nanosheet (SAuM) binds to free LPS, preventing free LPS from binding colistin and reducing endotoxemia (path b). This increases the antibacterial efficacy of colistin, decreasing both the required dose and the risk of resistance.

Abstract

A strong interaction between colistin, a last‐resort antibiotic of the polymyxin family, and free lipopolysaccharide (LPS, also referred to as endotoxin), released from the Gram‐negative bacterial (GNB) outer membrane (OM), has been identified that can decrease the antibacterial efficacy of colistin, potentially increasing the dose of this antibiotic required for treatment. The competition between LPS in the GNB OM and free LPS for the interaction with colistin was prevented by using a supramolecular trap to capture free LPS. The supramolecular trap, fabricated from a subnanometer gold nanosheet with methyl motifs (SAuM), blocks lipid A, preventing the interaction between lipid A and colistin. This can minimize endotoxemia and maximize the antibacterial efficacy of colistin, enabling colistin to be used at lower doses. Thus, the potential crisis of colistin resistance could be avoided.

Nature, Published online: 13 November 2019; doi:10.1038/s41586-019-1742-x

In patients with alcoholic hepatitis, cytolysin-positive Enterococcus faecalis strains are correlated with liver disease severity and increased mortality, and in mouse models these strains can be specifically targeted by bacteriophages.

Nature Microbiology, Published online: 04 November 2019; doi:10.1038/s41564-019-0591-6

Members of the Enterobacteriaceae, including adherent invasive Escherichia coli, reprogram their metabolism to preferentially consume dietary serine during periods of inflammation in the gut to promote their growth and outcompete other microbiome members.

Nature Chemical Biology, Published online: 04 November 2019; doi:10.1038/s41589-019-0393-4

A structural look at the interaction between the SH3b domain of the peptidoglycan endopeptidase lysostaphin and the target for its antistaphylococcal activity, peptidoglycan, reveals a mechanism of bacterial cell wall binding.

by Erica V. Harris, Jacobus C. de Roode, Nicole M. Gerardo

Abiotic and biotic factors can affect host resistance to parasites. Host diet and host gut microbiomes are two increasingly recognized factors influencing disease resistance. In particular, recent studies demonstrate that (1) particular diets can reduce parasitism; (2) diets can alter the gut microbiome; and (3) the gut microbiome can decrease parasitism. These three separate relationships suggest the existence of indirect links through which diets reduce parasitism through an alteration of the gut microbiome. However, such links are rarely considered and even more rarely experimentally validated. This is surprising because there is increasing discussion of the therapeutic potential of diets and gut microbiomes to control infectious disease. To elucidate these potential indirect links, we review and examine studies on a wide range of animal systems commonly used in diet, microbiome, and disease research. We also examine the relative benefits and disadvantages of particular systems for the study of these indirect links and conclude that mice and insects are currently the best animal systems to test for the effect of diet-altered protective gut microbiomes on infectious disease. Focusing on these systems, we provide experimental guidelines and highlight challenges that must be overcome. Although previous studies have recommended these systems for microbiome research, here we specifically recommend these systems because of their proven relationships between diet and parasitism, between diet and the microbiome, and between the microbiome and parasite resistance. Thus, they provide a sound foundation to explore the three-way interaction between diet, the microbiome, and infectious disease.

A membrane‐anchored photosensitizer, termed TBD‐anchor, capable of aggregation‐induced emission, generates ¹O₂ on the bacterial membrane. Over 99.8 % killing efficiency was obtained for methicillin‐resistant Staphylococcus aureus (MRSA) exposed to 0.8 μm of TBD‐anchor and white‐light irradiation. TBD‐anchor shows great promise as an effective antimicrobial agent for the treatment of antibiotic‐resistant bacterial infections.

Abstract

Traditional photosensitizers (PSs) show reduced singlet oxygen (¹O₂) production and quenched fluorescence upon aggregation in aqueous media, which greatly affect their efficiency in photodynamic therapy (PDT). Meanwhile, non‐targeting PSs generally yield low efficiency in antibacterial performance due to their short lifetimes and small effective working radii. Herein, a water‐dispersible membrane anchor (TBD‐anchor) PS with aggregation‐induced emission is designed and synthesized to generate ¹O₂ on the bacterial membrane. TBD‐anchor showed efficient antibacterial performance towards both Gram‐negative (Escherichia coli) and Gram‐positive bacteria (Staphylococcus aureus). Over 99.8 % killing efficiency was obtained for methicillin‐resistant S. aureus (MRSA) when they were exposed to 0.8 μm of TBD‐anchor at a low white light dose (25 mW cm⁻²) for 10 minutes. TBD‐anchor thus shows great promise as an effective antimicrobial agent to combat the menace of multidrug‐resistant bacteria.

Nature, Published online: 30 October 2019; doi:10.1038/s41586-019-1708-z

An interbacterial defence strategy, involving clusters of immunity genes against toxins released by the type VI secretion system of the same or different species, is widespread among Bacteroides species, and transfer of these gene clusters confers resistance to toxins in vitro and in the mammalian gut.

Many multidomain proteins contain disordered linkers that regulate interdomain contacts, and thus the effective concentrations that govern intramolecular reactions. Effective concentrations are rarely measured experimentally, and therefore little is known about how they relate to linker architecture. We have directly measured the effective concentrations enforced by disordered protein linkers using...

Nature Microbiology, Published online: 28 October 2019; doi:10.1038/s41564-019-0595-2

A modified mouse model that mimics human serum levels of biotin shows that inhibition of biotin synthesis can effectively treat infections caused by diverse antibiotic-resistant pathogens.

Nature Chemistry, Published online: 28 October 2019; doi:10.1038/s41557-019-0351-5

A set of enantioprobes—photoreactive, clickable fragment pairs differing only in absolute stereochemistry—have been used to provide a robust and streamlined chemical proteomic map of small-molecule/protein interactions in human cells. More than 170 stereoselective fragment–protein interactions were discovered and shown to occur at functional sites on proteins from diverse classes.

Co-translational processes in bacteria are attractive drug targets, but while some processes are essential, others are not. The essentiality of Peptide Deformylase (PDF, def) for vitality of mycobacteria was spec...

Nature, Published online: 23 October 2019; doi:10.1038/d41586-019-03114-1

Microorganisms in the gut influence fear-related learning. The results of a study that reveals some of the mechanistic underpinnings of this phenomenon promise to boost our understanding of gut–brain communication.

Nature, Published online: 23 October 2019; doi:10.1038/s41586-019-1665-6

A class of chimeric synthetic antibiotics that bind to lipopolysaccharide and BamA shows potent activity against multidrug-resistant Gram-negative bacteria, with the potential to address life-threatening infections.

A reshaped version of the endogenous siderocalin (right) binds petrobactin from B. anthracis (left) instead of enterobactin. Thus, it can effectively suppress the growth of corresponding pathogenic bacteria by depriving them of their iron supply and has the potential to complement antibiotic therapy in situations of acute or persistent infection.

Abstract

Iron acquisition mediated by siderophores, high‐affinity chelators for which bacteria have evolved specific synthesis and uptake mechanisms, plays a crucial role in microbiology and in host–pathogen interactions. In the ongoing fight against bacterial infections, this area has attracted biomedical interest. Beyond several approaches to interfere with siderophore‐mediated iron uptake from medicinal and immunochemistry, the development of high‐affinity protein scavengers that tightly complex the siderophores produced by pathogenic bacteria has appeared as a novel strategy. Such binding proteins have been engineered based on siderocalin—also known as lipocalin 2—an endogenous human scavenger of enterobactin and bacillibactin that controls the systemic spreading of commensal bacteria such as Escherichia coli. By using combinatorial protein design, siderocalin was reshaped to bind several siderophores from Pseudomonas aeruginosa and, in particular, petrobactin from Bacillus anthracis, none of which is recognized by the natural protein. Such engineered versions of siderocalin effectively suppress the growth of corresponding pathogenic bacteria by depriving them of their iron supply and offer the potential to complement antibiotic therapy in situations of acute or persistent infection.

Expanding the bioorthogonal toolbox: Reaction development and kinetic analysis of the cycloaddition between nitrones and trans‐cyclooctenes (TCOs) demonstrates the utility of this reaction for bioorthogonal labelling. By using TCOs and nitrones as reagents, robust labelling of the bacterial peptidoglycan layer is achieved, thus demonstrating this reaction as a new bioorthogonal ligation tool.

Abstract

Trans‐cyclooctenes (TCOs) represent interesting and highly reactive dipolarophiles for organic transformations including bioorthogonal chemistry. Herein we show that TCOs react rapidly with nitrones and that these reactions are bioorthogonal. Kinetic analysis of acyclic and cyclic nitrones with strained‐trans‐cyclooctene (s‐TCO) shows fast reactivity and demonstrates the utility of this cycloaddition reaction for bioorthogonal labelling. Labelling of the bacterial peptidoglycan layer with unnatural d‐amino acids tagged with nitrones and s‐TCO‐Alexa488 is demonstrated. These new findings expand the bioorthogonal toolbox, and allow TCO reagents to be used in bioorthogonal applications beyond tetrazine ligations for the first time and open up new avenues for bioorthogonal ligations with diverse nitrone reactants.

ABSTRACT

Osteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. OM is predominantly caused by Staphylococcus aureus, and even with proper treatment, OM has a high rate of recurrence and chronicity. While S. aureus has been shown to infect osteoblasts, it remains unclear whether osteoclasts (OCs) are also a target of intracellular infection. Here, we demonstrate the ability of S. aureus to intracellularly infect and divide within OCs. OCs were differentiated from bone marrow macrophages (BMMs) by exposure to receptor activator of nuclear factor kappa-B ligand (RANKL). By utilizing an intracellular survival assay and flow cytometry, we found that at 18 h postinfection the intracellular burden of S. aureus increased dramatically in cells with at least 2 days of RANKL exposure, while the bacterial burden decreased in BMMs. To further explore the signals downstream of RANKL, we manipulated factors controlling OC differentiation, NFATc1 and alternative NF-B, and found that intracellular bacterial growth correlates with NFATc1 levels in RANKL-treated cells. Confocal and time-lapse microscopy in mature OCs showed a range of intracellular infection that correlated inversely with S. aureus-phagolysosome colocalization. The propensity of OCs to become infected, paired with their diminished bactericidal capacity compared to BMMs, could promote OM progression by allowing S. aureus to evade initial immune regulation and proliferate at the periphery of lesions where OCs are most abundant.

IMPORTANCE The inflammation of bone tissue is called osteomyelitis, and most cases are caused by an infection with the bacterium Staphylococcus aureus. To date, the bone-building cells, osteoblasts, have been implicated in the progression of these infections, but not much is known about how the bone-resorbing cells, osteoclasts, participate. In this study, we show that S. aureus can infect osteoclasts and proliferate inside these cells, whereas bone-residing macrophages, immune cells related to osteoclasts, destroy the bacteria. These findings elucidate a unique role for osteoclasts to harbor bacteria during infection, providing a possible mechanism by which bacteria could evade destruction by the immune system.

Nature Microbiology, Published online: 14 October 2019; doi:10.1038/s41564-019-0581-8

Host mucin glycans downregulate virulence processes of Pseudomonas aeruginosa and can be used therapeutically to attenuate infection in vivo in a burn wound model.

A bacterium can protect against rotavirus infection in mice independent of the immune system.

The development of new antimicrobial drugs is a priority to combat the increasing spread of multidrug-resistant bacteria. This development is especially problematic in gram-negative bacteria due to the outer membrane (OM) permeability barrier and multidrug efflux pumps. Therefore, we screened for compounds that target essential, nonredundant, surface-exposed processes in gram-negative...

Bacterial outer membrane vesicles (OMVs) represent an interesting vaccine platform for their built-in adjuvanticity and simplicity of production process. Moreover, OMVs can be decorated with foreign antigens using different synthetic biology approaches. However, the optimal OMV engineering strategy, which should guarantee the OMV compartmentalization of most heterologous antigens in quantities...

Antibiotics induce large and highly variable changes in the intestinal microbiome even at sublethal concentrations, through mechanisms that remain elusive. Using gnotobiotic zebrafish, which allow high-resolution examination of microbial dynamics, we found that sublethal doses of the common antibiotic ciprofloxacin cause severe drops in bacterial abundance. Contrary to conventional views...