LAUSR

The spread of antibiotic resistance is one of the most serious global public-health problems. Here we show that a particular class of homomers with binding sites spanning multiple protein chains is particularly suitable for targeting by broad-spectrum antibacterial agents because due to the slow evolutionary change of such binding pockets, ligands of such homomers are much more likely to bind their homologs than ligands of monomers, or homomers with a single-chain binding site. Additionally, using de novo ligand design and deep learning, we show that the chemical compounds that can bind several different receptors have common structural characteristics and that halogens and fragments similar to the building blocks existing antimicrobials are overrepresented in them. Finally, we show that binding multiple receptors selects for flexible compounds, which are less likely to accumulate in Gram-negative bacteria; thus there is trade-off between reducing the emergence of resistance by multitargeting and broad-spectrum antibacterial activity.