Molecular basis for inhibition of adhesin-mediated bacterial-host interactions through a novel peptide-binding domain

Abstract

AbstractModulation of protein-protein interactions (PPIs) with small-molecules is a promising conceptual approach in drug discovery. In the area of bacterial colonization, PPIs contribute to adhesin-mediated biofilm formation that cause most infections. However, the molecular basis underlying these adhesin-ligand interactions is largely unknown. The 1.5-MDa adhesion protein, MpIBP, uses a peptide-binding domain (MpPBD) to help its Antarctic bacterium form symbiotic biofilms on sea ice with microalgae such as diatoms. X-ray crystallography revealed MpPBD uses Camdependent interactions to self-associate with a crystal symmetry mate via the C-terminal threonine-proline-aspartate sequence. Structure-guided optimization derived penta-peptide ligands that bound MpPBD 1,000-fold more tightly, with affinities in the nano-molar range. These ligands act as potent antagonists to block MpPBD from binding to the diatom cells. Since adhesins of some human pathogens contain peptide-binding module homologs of MpPBD, this same conceptual approach could help develop ligand-based PPI modulators to disrupt harmful bacteria-host interactions.