Marcos Pires

Nature, Published online: 03 January 2024; doi:10.1038/d41586-023-03988-2

Infections caused by drug-resistant strains of the bacterium Acinetobacter baumannii have been hard to treat in the clinic. A new class of antibiotics has been identified with the potential to tackle these microbes.

Nature, Published online: 03 January 2024; doi:10.1038/s41586-023-06873-0

A tethered macrocyclic peptide antibiotic class described here—which shows potent antibacterial activity against carbapenem-resistant Acinetobacter baumannii—blocks the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane through inhibition of the LptB2FGC complex.

Nature, Published online: 03 January 2024; doi:10.1038/s41586-023-06799-7

A mechanism of lipid transport inhibition has been identified for a class of peptide antibiotics effective against resistant Acinetobacter strains, which may have applications in the inhibition of other Gram-negative pathogens.

Nature Chemical Biology, Published online: 28 December 2023; doi:10.1038/s41589-023-01496-y

Cyclic peptides show promise for modulating difficult disease targets; however, they often cannot be administered orally. The authors developed a method to synthesize and screen large libraries of small cyclic peptides while enabling the simultaneous interrogation of activity and permeability. This approach was applied to the disease target thrombin to discover peptides with high affinity, stability and oral bioavailability of up to 18% in rats.

Nature Chemical Biology, Published online: 07 December 2023; doi:10.1038/s41589-023-01495-z

Macrocyclic peptides are promising scaffolds for chemical tools and potential therapeutics, but their synthesis is currently difficult. Here, the authors report the characterization of Ulm16, a peptide cyclase of the penicillin-binding protein (PBP)-type class of thioesterases, that catalyzes head-to-tail macrolactamization of nonribosmal peptides of 4–6 amino acids in length.

Staphylococcus aureus can persist within host immune cells, potentially evading immune responses and antibiotics. Investigating antibiotic permeability into phagocytic vacuoles, we developed a permeability assay. By analyzing antibiotic arrival in phagosomes of infected macrophages, we identified permeability differences, offering insights into antibiotic contribution to intracellular pathogens.

Abstract

Staphylococcus aureus (S. aureus) has evolved the ability to persist after uptake into host immune cells. This intracellular niche enables S. aureus to potentially escape host immune responses and survive the lethal actions of antibiotics. While the elevated tolerance of S. aureus to small-molecule antibiotics is likely to be multifactorial, we pose that there may be contributions related to permeation of antibiotics into phagocytic vacuoles, which would require translocation across two mammalian bilayers. To empirically test this, we adapted our recently developed permeability assay to determine the accumulation of FDA-approved antibiotics into phagocytic vacuoles of live macrophages. Bioorthogonal reactive handles were metabolically anchored within the surface of S. aureus, and complementary tags were chemically added to antibiotics. Following phagocytosis of tagged S. aureus cells, we were able to specifically analyze the arrival of antibiotics within the phagosomes of infected macrophages. Our findings enabled the determination of permeability differences between extra- and intracellular S. aureus, thus providing a roadmap to dissect the contribution of antibiotic permeability to intracellular pathogens.

Nature, Published online: 22 November 2023; doi:10.1038/s41586-023-06760-8

We use a whole-cell accumulation assay to assess the ability of non-antibiotic, structurally diverse small molecules to accumulate in Pseudomonas aeruginosa, with potential application in developing drugs to target this pathogen.

Nature Immunology, Published online: 12 October 2023; doi:10.1038/s41590-023-01645-4

Here, the authors show that deletion of Pglyrp1 promotes antitumor immunity owing to its inhibitory function in CD8+ T cells and that targeting it can inhibit development of autoimmune neuroinflammation. These findings indicate that PGLYRP1 might be a target for immunotherapy.

Clovibactin, a new antibiotic isolated from soil bacteria, blocks bacterial cell wall synthesis by targeting essential peptidoglycan precursors, allowing it to kill drug-resistant bacterial pathogens without detectable resistance.

Proceedings of the National Academy of Sciences, Volume 120, Issue 25, June 2023.

Nature, Published online: 17 May 2023; doi:10.1038/s41586-023-06081-w

Tumour-infiltrating lymphocytes from glioblastoma can recognize bacterial and gut microbial peptides.

Papadopoulou et al. target the two main barriers to successful antibiotic chemotherapy against biofilms: poor drug penetration and persister cells. Utilizing sonobactericide to improve penetration of an anti-persister drug combination greatly enhanced therapeutic clearance in a diabetic wound infection model.

Homo-dimeric BacPROTACs induce the self-degradation of essential Clp components of the mycobacterial proteostasis system, introducing a potent antibiotic strategy against M. tuberculosis.

A commensal bacterium exploits phase separation of a transcription termination factor to colonize the gut.

Metabolite-induced cysteine carboxyethylation generates neoantigens that may fuel autoimmunity.

Proceedings of the National Academy of Sciences, Volume 120, Issue 11, March 2023.

Peptides are used in place of oligonucleotides to tag libraries of small-molecule drug candidates for affinity selection.

Nature, Published online: 01 March 2023; doi:10.1038/s41586-023-05750-0

A study demonstrates that specific interactions between the two committed enzymes for the synthesis of lipopolysaccharide and peptidoglycan enable coordinated assembly of the outer membrane and cell wall in the Gram-negative pathogen Pseudomonas aeruginosa.