Ligands and Receptors with Broad Binding Capabilities Have Common Structural Characteristics: An Antibiotic Design Perspective

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.