Marcos Pires

Thermostabilization represents a critical and often obligatory step toward enhancing the robustness of enzymes for organic synthesis and other applications. While directed evolution methods have provided valuable tools for this purpose, these protocols are laborious and time-consuming and typically require the accumulation of several mutations, potentially at the expense of...

Mass spectrometry imaging (MSI) was used to elucidate host lipids involved in the inflammatory signaling pathway generated at the host–pathogen interface during a septic bacterial infection. Using Francisella novicida as a model organism, a bacterial lipid virulence factor (endotoxin) was imaged and identified along with host phospholipids involved in the...

Abstract

Protein-protein interactions mediate essential biological processes, but characterizing these interactions in cells presents a major challenge. Kleiner et al. describe a chemical proteomics approach combining photo-crosslinking and SILAC-based proteomics to characterize context-dependent direct protein-protein interactions in live cells. They apply their approach to profile interactions involving core histones H3 and H4.

Using statins to disassemble bacterial membrane microdomains can decrease antibiotic resistance and re-sensitize MRSA to antibiotic therapies in vivo.

Immunotherapies, particularly checkpoint inhibitors, have set off a revolution in cancer therapy by releasing the power of the immune system. However, only little is known about the antigens that are essentially presented on cancer cells, capable of exposing them to immune cells. Large-scale HLA ligandome analysis has enabled us to...

ABSTRACT

Gram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species. We report that in significant human pathogens Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia spp., the differences in antibiotic resistance are largely defined by their penetration into the cell. For all tested antibiotics, the intracellular penetration was determined by a synergistic relationship between active efflux and the permeability barrier. We found that the outer membrane (OM) and efflux pumps select compounds on the basis of distinct properties and together universally protect bacteria from structurally diverse antibiotics. On the basis of their interactions with the permeability barriers, antibiotics can be divided into four clusters that occupy defined physicochemical spaces. Our results suggest that rules of intracellular penetration are intrinsic to these clusters. The identified specificities in the permeability barriers should help in the designing of successful therapeutic strategies against antibiotic-resistant pathogens.

IMPORTANCE Multidrug-resistant strains of Gram-negative pathogens rapidly spread in clinics. Significant efforts worldwide are currently directed to finding the rules of permeation of antibiotics across two membrane envelopes of these bacteria. This study created the tools for analysis of and identified the major differences in antibacterial activities that distinguish the permeability barriers of P. aeruginosa, A. baumannii, Burkholderia thailandensis, and B. cepacia. We conclude that synergy between active efflux and the outer membrane barrier universally protects Gram-negative bacteria from antibiotics. We also found that the diversity of antibiotics affected by active efflux and outer membrane barriers is broader than previously thought and that antibiotics cluster according to specific biological determinants such as the requirement of specific porins in the OM, targeting of the OM, or specific recognition by efflux pumps. No universal rules of antibiotic permeation into Gram-negative bacteria apparently exist. Our results suggest that antibiotic clusters are defined by specific rules of permeation and that further studies could lead to their discovery.

DISARM is a widespread bacterial defence system with broad anti-phage activities

DISARM is a widespread bacterial defence system with broad anti-phage activities, Published online: 30 October 2017; doi:10.1038/s41564-017-0051-0

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A widespread anti-phage defence system, DISARM (defence island system associated with restriction–modification), is identified.

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Gale et al. reconstitute WTA transfer to peptidoglycan in vitro using B. subtilis LCP enzymes and probe catalytic requirements along with substrate preferences, providing the first detailed biochemical characterization of these enzymes.

Unlike their descendants, mitochondria and plastids, bacteria do not have dedicated protein import systems. However, paradoxically, import of protein bacteriocins, the mechanisms of which are poorly understood, underpins competition among pathogenic and commensal bacteria alike. Here, using X-ray crystallography, isothermal titration calorimetry, confocal fluorescence microscopy, and in vivo photoactivatable cross-linking...

Nature advance online publication 25 October 2017. doi:10.1038/nature24157

Author: John D. MacMicking

Infection with Shigella flexneri bacteria is a major cause of infant death. It emerges that S. flexneri evades intracellular defences by releasing a protein that triggers the destruction of members of a key family of host enzymes.

Characterization of a wild mice reference microbiome opens a window of opportunity to understand how the gut microbiota affects aspects of host physiology that are important in the natural world outside the laboratory.

Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) mainly in young adults, and a breakage of immune tolerance to CNS self-antigens has been suggested to initiate CNS autoimmunity. Age and microbial infection are well-known factors involved in the development of autoimmune diseases, including MS. Recent...

Self-sensing in Bacillus subtilis quorum-sensing systems

Nature Microbiology, Published online: 16 October 2017; doi:10.1038/s41564-017-0044-z

Bacillus subtilis cells are able to sense self-produced autoinducers, which gives rise to stronger quorum-sensing-mediated responses, in a process that can influence the generation of persisters during antibiotic treatment.

Structural basis for maintenance of bacterial outer membrane lipid asymmetry

Nature Microbiology, Published online: 16 October 2017; doi:10.1038/s41564-017-0046-x

The crystal structure of MlaA, coupled with simulations of its interaction with phospholipids, elucidates how this outer membrane lipoprotein acts as a phospholipid translocation channel to maintain the asymmetric composition of the outer membrane.

D-Alanylation of teichoic acids contributes to Lactobacillus plantarum-mediated Drosophila growth during chronic undernutrition

Nature Microbiology, Published online: 9 October 2017; doi:10.1038/s41564-017-0038-x

Under nutritional limitation, modification of the Lactobacillus plantarum cell wall by d-alanylation of teichoic acids is important for host intestinal peptidase expression and consequently growth of the Drosophila host, providing further insights into host–commensal interactions.

Abstract

Receptor tyrosine kinases operate under principles of biased agonism to shape signaling outputs.

Fluorescent D-amino-acids reveal bi-cellular cell wall modifications important for Bdellovibrio bacteriovorus predation

Nature Microbiology, Published online: 3 October 2017; doi:10.1038/s41564-017-0029-y

Fluorescent d-amino acid incorporation reveals host–prey cell wall modification during Bdellovibrio bacteriovorus predation including pore formation and l,d-transpeptidase-mediated prey strengthening.

Mycobacterium tuberculosis is a major human pathogen that is able to survive inside host cells and resist immune clearance. Most particularly, it inhibits several arms of the innate immune response, including phagosome maturation or cytokine production. To better understand the molecular mechanisms by which M. tuberculosis circumvents host immune defenses,...