In most cases, antibiotics are a reliable form of protection against bacterial infections. They have saved billions of human lives since their introduction.

The human pathogen Pseudomonas aeruginosa is particularly notorious for its multiple resistance mechanisms. A new concept for anti-infectives is the “pathoblocker” approach, which targets virulence factors to disarm rather than kill pathogens and thus attenuates the development of resistance. Based on the estrogen receptor modulator raloxifene, which had previously been identified as a potential biosynthesis inhibitor of the virulence factor pyocyanin via in silico screening, analogues have been developed as pathoblockers against P. aeruginosa. These compounds reduce the production of pyocyanin by binding to the phenazine biosynthesis enzyme PhzB. Structure–activity relationships (SAR) were explored using nano differential scanning fluorimetry, isothermal titration calorimetry, and 12 X-ray cocrystal structures. Compared to raloxifene, congener 20c shows a 60-fold lower affinity for the human estrogen receptor with a 15-fold increase in pyocyanin inhibitory activity. The comprehensive structural information gathered in this study paves the way for the development of improved pathoblockers with increased potency and selectivity.

Staphylococcus aureus is a major pathogen with rising antibiotic resistance. In this issue of Cell Host & Microbe, Shekhar et al. find that quinoxalinediones reduce S. aureus lung infections through α...

Staphylococcus aureus is a major pathogen with rising antibiotic resistance. In this issue of Cell Host & Microbe, Shekhar et al. find that quinoxalinediones reduce S. aureus lung infections through α-hemolysin inhibition, offering a therapeutic strategy for S. aureus pneumonia.

Communications Chemistry, Published online: 11 April 2025; doi:10.1038/s42004-025-01484-4Computational prediction of molecular properties is emerging as a key component for streamlining drug development. Here, the authors report ChemLM, a transformer language model that leverages self-supervised domain adaptation on chemical molecules to enhance the predictive performance, demonstrating high accuracy in identifying highly potent pathoblockers against Pseudomonas aeruginosa.

Glycan epitopes exposed on the host cell surface serve as receptors for a wide range of proteins expressed by microorganisms. Among these, lectins that are produced by viruses, bacteria, and fungi in either soluble or surface-attached forms, play key roles in infection processes. The fine specificity that many of these glycan-binding proteins display toward human glycan epitopes is the result of long-term co-evolution. Structural insights into lectin architecture, their binding sites, and the atomic details of their interactions with glycans are crucial for designing antimicrobial agents capable of competing with infectious processes and potentially supplementing antibiotics in the current fight against antimicrobial resistance. This review highlights how structural lectinology can serve as a starting point for fruitful collaborations with synthetic carbohydrate chemists in the design, synthesis, and characterization of glycomimetics acting as pathoblockers. Various strategies have been developed to target lectins, exemplified here by soluble lectins from the lung pathogens Pseudomonas aeruginosa and members of the Burkholderia cepacia complex. The affinity for monosaccharide ligands has been enhanced through heterocyclic functionalization using classical medicinal chemistry approaches, with the best results obtained by mimicking natural glycan receptors. Alternatively, the oligomeric nature of lectins allows the design of divalent or multivalent ligands, which exhibit much stronger affinity due to the cluster effect. Covalent inhibitors and non-carbohydrate glycomimetics also represent promising leads for future strategies to combat antimicrobial resistance.

Staphylococcus aureus is a major pathogen with rising antibiotic resistance. In this issue of Cell Host & Microbe, Shekhar et al. find that quinoxalinediones reduce S. aureus lung infections through α...