Marcos Pires

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.

Macrolides generally have low efficacy against tuberculosis, but a class of macrolides called “sequanamycins” overcomes the resistance of Mycobacterium tuberculosis to macrolides and can be optimized for potent activity against a variety of Mycobacterium tuberculosis strains, including drug-resistant ones.

Proceedings of the National Academy of Sciences, Volume 120, Issue 7, February 2023.

Nature Cell Biology, Published online: 30 January 2023; doi:10.1038/s41556-022-01077-6

Contraction of the hair follicle-lining dermal sheath smooth muscle generates the forces necessary for the tissue remodelling that takes place during the regression phase of the hair growth cycle. This study reveals that endothelin signalling — from epithelial progenitors at the follicle bottleneck region to its neighbouring dermal sheath — is the main contraction-activating pathway.

We describe a method to systematically address the structural determinants of permeability in Mtb. This workflow, Peptidoglycan Accessibility Click-Mediated AssessmeNt (PAC-MAN), provides a screening platform to measure the permeation of any molecule that is modified with a small azide handle. When molecules reach the peptidoglycan layer, they react with DBCO (site selectively anchored by metabolic labeling), thus imprinting their permeation.

Abstract

The general lack of permeability of small molecules observed for Mycobacterium tuberculosis (Mtb) is most ascribed to its unique cell envelope. More specifically, the outer mycomembrane is hypothesized to be the principal determinant for access of antibiotics to their molecular targets. We describe a novel assay that combines metabolic tagging of the peptidoglycan, which sits directly beneath the mycomembrane, click chemistry of test molecules, and a fluorescent labeling chase step, to measure the permeation of small molecules. We showed that the assay workflow was robust and compatible with high-throughput analysis in mycobacteria by testing a small panel of azide-tagged molecules. The general trend is similar across the two types of mycobacteria with some notable exceptions. We anticipate that this assay platform will lay the foundation for medicinal chemistry efforts to understand and improve uptake of both existing drugs and newly-discovered compounds into mycobacteria.

Proceedings of the National Academy of Sciences, Volume 120, Issue 4, January 2023.

Nature Communications, Published online: 24 December 2022; doi:10.1038/s41467-022-35607-5

Some bacteria use the muropeptide transporter AmpG for uptake and recycling of cell wall fragments that are released during cell growth and division. Here, Gilmore & Cava show that the plant pathogen Agrobacterium tumefaciens, which lacks an AmpG homologue, uses a different type of transporter for the same function, which is essential for normal growth in this organism.

Nature Chemical Biology, Published online: 28 December 2022; doi:10.1038/s41589-022-01218-w

Discovery of macrocyclic ligands to the 19S regulatory particle protein PSMD2 enables the synthesis of heterobifunctional molecules that demonstrate proof-of-concept, targeted degradation of BRD4 through direct engagement of the 26S proteasome.

Chemical-genetic approaches elucidate the uptake pathway for molecules that break traditional drug design rules.

Nature Chemistry, Published online: 03 October 2022; doi:10.1038/s41557-022-01048-2

Tigilanol tiglate is a therapeutic lead for the treatment of a broad range of cancers. Now, it has been shown that tigilanol tiglate can be synthesized in a time and step economical fashion from phorbol—its naturally abundant biosynthetic precursor. This synthesis provides rapid access to analogues with unprecedented protein kinase C binding activity.

Nature Chemical Biology, Published online: 29 September 2022; doi:10.1038/s41589-022-01122-3

Chemoproteomic analysis reveals that anti-infective bile acids directly bind and inactivate a transcriptional regulator of Salmonella virulence.

Nature, Published online: 21 September 2022; doi:10.1038/s41586-022-05235-6

Membrane-bound E3 ubiquitin ligases RNF43 and ZNRF3 are overexpressed in colorectal cancer, and can be repurposed using proteolysis-targeting antibodies (PROTABs) to selectively degrade cell-surface receptors in tumours.

Nature, Published online: 15 June 2022; doi:10.1038/s41586-022-04834-7

Peptidoglycan stem peptides in the Gram-negative bacterial cell wall regulate the insertion of essential outer membrane proteins, thus representing a potential target for antibiotic design.

Nature, Published online: 15 June 2022; doi:10.1038/s41586-022-04839-2

A newly developed genetically engineered mouse model enables the analysis of specific antigen presentation in vivo, providing insights into the tumour immunopeptidome and cancer progression.

Small-molecule adaptors, BacPROTACs, redirect bacterial ClpCP protease to target neo-substrates in a highly specific manner and expand targeted protein degradation technology to bacteria.

Nature, Published online: 08 June 2022; doi:10.1038/s41586-022-04801-2

Synthetic chimeric orthogonal IL-2 receptors that incorporate the intracellular domain of receptors for other γ-chain cytokines such as IL-9 can reroute orthogonal signalling and alter the phenotype of T cells to improve anti-tumour responses.