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Cell Sep 2023Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria....
Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (CPP, lipid II, and lipid III). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development.
Topics: Anti-Bacterial Agents; Bacteria; Biological Assay; Diphosphates; Soil Microbiology
PubMed: 37611581
DOI: 10.1016/j.cell.2023.07.038 -
Nature Immunology Nov 2023Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint...
Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint blockade is a successful treatment option for multiple human cancers, severe autoimmune-like adverse effects can limit its application. Here, we show that the gene encoding peptidoglycan recognition protein 1 (PGLYRP1) is highly coexpressed with genes encoding co-inhibitory molecules, indicating that it might be a promising target for cancer immunotherapy. Genetic deletion of Pglyrp1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8 T cells, suggesting an inhibitory function of PGLYRP1 in CD8 T cells. Surprisingly, genetic deletion of Pglyrp1 protected against the development of experimental autoimmune encephalomyelitis, a model of autoimmune disease in the central nervous system. PGLYRP1-deficient myeloid cells had a defect in antigen presentation and T cell activation, indicating that PGLYRP1 might function as a proinflammatory molecule in myeloid cells during autoimmunity. These results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Immunotherapy; Inflammation; Neoplasms; Neuroinflammatory Diseases; Tumor Microenvironment
PubMed: 37828379
DOI: 10.1038/s41590-023-01645-4 -
Nature Communications Oct 2023Peptidoglycan, a gigadalton polymer, functions as the scaffold for bacterial cell walls and provides cell integrity. Peptidoglycan is remodelled by a large and diverse...
Peptidoglycan, a gigadalton polymer, functions as the scaffold for bacterial cell walls and provides cell integrity. Peptidoglycan is remodelled by a large and diverse group of peptidoglycan hydrolases, which control bacterial cell growth and division. Over the years, many studies have focused on these enzymes, but knowledge on their action within peptidoglycan mesh from a molecular basis is scarce. Here, we provide structural insights into the interaction between short peptidoglycan fragments and the entire sacculus with two evolutionarily related peptidases of the M23 family, lysostaphin and LytM. Through nuclear magnetic resonance, mass spectrometry, information-driven modelling, site-directed mutagenesis and biochemical approaches, we propose a model in which peptidoglycan cross-linking affects the activity, selectivity and specificity of these two structurally related enzymes differently.
Topics: Humans; Staphylococcus aureus; Peptidoglycan; Hydrolases; Lysostaphin; Mass Spectrometry; Staphylococcal Infections; Cell Wall
PubMed: 37872144
DOI: 10.1038/s41467-023-42506-w -
Nature Communications Aug 2023The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence,...
The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence, Bcc species are notorious for causing recalcitrant multidrug-resistant infections in immunocompromised individuals. Here, we present the results of a genome-wide screen for cell envelope-associated resistance and susceptibility determinants in a Burkholderia cenocepacia clinical isolate. For this purpose, we construct a high-density, randomly-barcoded transposon mutant library and expose it to 19 cell envelope-targeting antibiotics. By quantifying relative mutant fitness with BarSeq, followed by validation with CRISPR-interference, we profile over a hundred functional associations and identify mediators of antibiotic susceptibility in the Bcc cell envelope. We reveal connections between β-lactam susceptibility, peptidoglycan synthesis, and blockages in undecaprenyl phosphate metabolism. The synergy of the β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is primarily mediated by inhibition of the PenB carbapenemase. In comparison with ceftazidime, avibactam more strongly potentiates the activity of aztreonam and meropenem in a panel of Bcc clinical isolates. Finally, we characterize in Bcc the iron and receptor-dependent activity of the siderophore-cephalosporin antibiotic, cefiderocol. Our work has implications for antibiotic target prioritization, and for using additional combinations of β-lactam/β-lactamase inhibitors that can extend the utility of current antibacterial therapies.
Topics: Humans; Anti-Bacterial Agents; Ceftazidime; beta-Lactamase Inhibitors; Meropenem; beta-Lactamases; Drug Combinations; Microbial Sensitivity Tests
PubMed: 37558695
DOI: 10.1038/s41467-023-40494-5 -
Pathogens (Basel, Switzerland) Jun 2023Probiotics are being used as feed/food supplements as an alternative to antibiotics. It has been demonstrated that probiotics provide several health benefits, including... (Review)
Review
Probiotics are being used as feed/food supplements as an alternative to antibiotics. It has been demonstrated that probiotics provide several health benefits, including preventing diarrhea, irritable bowel syndrome, and immunomodulation. Alongside probiotic bacteria-fermented foods, the different structural components, such as lipoteichoic acids, teichoic acids, peptidoglycans, and surface-layer proteins, offer several advantages. Probiotics can produce different antimicrobial components, enzymes, peptides, vitamins, and exopolysaccharides. Besides live probiotics, there has been growing interest in consuming inactivated probiotics in farm animals, including pigs. Several reports have shown that live and killed probiotics can boost immunity, modulate intestinal microbiota, improve feed efficiency and growth performance, and decrease the incidence of diarrhea, positioning them as an interesting strategy as a potential feed supplement for pigs. Therefore, effective selection and approach to the use of probiotics might provide essential features of using probiotics as an important functional feed for pigs. This review aimed to systematically investigate the potential effects of lactic acid bacteria in their live and inactivated forms on pigs.
PubMed: 37513721
DOI: 10.3390/pathogens12070874 -
ELife Apr 2024An enzyme that remodels the cell wall of helps these gut bacteria to divide and generate peptide fragments that enhance the immune response against cancer.
An enzyme that remodels the cell wall of helps these gut bacteria to divide and generate peptide fragments that enhance the immune response against cancer.
PubMed: 38578679
DOI: 10.7554/eLife.97277