Biophysical strategies to inhibit bacterial amyloid formation and undermine biofilm infections

Abstract

When bacteria dwell in biofilms on the surface of an implanted medical device or surgical site, cells co-associate using a self-produced extracellular matrix (EM), which acts as a layer of protection against antibiotic infiltration. The EM is comprised of polysaccharides, DNA, and proteins including amyloid fibrils. Extracellular deposition of amyloid has long been associated with protein misfolding and neurodegenerative diseases, but a growing body of research demonstrates that bacteria have adopted amyloid fibrils as a functional scaffold to reinforce the biofilm. Consequently, these functional amyloids represent a novel target to interrupt biofilm formation and address the problems of biofilm-associated infection and resistance. The pathway to amyloid formation in the EM is characterized by specific physicochemical motifs; therefore, peptides engineered to bind these motifs should inhibit fibril formation and disrupt biofilm development. Here, the mechanism of amyloid formation is analyzed in both Gram positive and Gram negative bacteria, peptide design approaches are introduced to inhibit amyloid formation, and the results are translated to clinically relevant models.