Molecular strategy for blocking isopeptide bond formation in nascent pilin proteins

• DOI: 10.1073/pnas.1807689115
• Publication Date: 2018-08-28T00:15:37Z
• Authors: Jaime Andrés Riva...; Carmen L. Badilla; Rafael Tapia-Rojo; Álvaro Alonso-Cab...; Julio M. Fernández
• Keywords: 0301 basic medicine; Protein Folding; 0303 health sciences; 03 medical and health sciences; Protein Domains; Protein Stability; Streptococcus pyogenes; Humans; Fimbriae Proteins; Peptides; Anti-Bacterial Agents

Significance At the onset of an infection, gram-positive bacteria adhere to host cells through their pili, filamentous structures built by hundreds of repeats of pilin proteins. These proteins can withstand large mechanical challenges without unfolding, remaining anchored to the host and resisting cleavage by proteases and oxygen radicals present in the targeted tissues. The key structural component that gives pilins mechanical resilience are internal isopeptide bonds, strategically placed so that pilins become inextensible structures. We target this bond by designing a blocking peptide that interferes with its formation during folding. We demonstrate that peptide-modified pilins lack mechanical stability and extend at low forces. We propose this strategy as a rational design of mechanical antibiotics, targeting the Achilles heel of bacterial adhesion.