New Structure-Activity Paradigms for Amyloids from Pathogenic Microbes

Microbial functional amyloids are structured protein aggregates serving specific and highly diverse functions, including biofilm structuring and interactions with the host. Despite their role as key virulence factors and antimicrobial drug targets, amyloids are mostly known for their involvement in fatal human aggregation diseases, and their structures have been studied only in eukaryotes. To bridge this informational gap, we used methods of X-ray microcrystallography to shed light on this unheeded aspect of microbial physiology and functional fibrils. This allowed us to correlate specific structural features of various amyloid states to dedicated biological functions. We discovered unique amyloid-like structures, including, to our surprise, a structure of a full-length bacterial cross-alpha amyloid-like fibril which is unprecedented in >100 structures of eukaryotic cross-beta amyloids solved to date. The fibrils, of the PSMα3 peptide secreted by Staphylococcus aureus, are toxic to human cells, clarifying their involvement in pathogenicity (Tayeb-Fligelman et. al., Science 355(6327): 831-833; 2017). Given our results we predict that the structural and functional repertoire of amyloids is far more diverse than previously anticipated, providing a rich source of targets for antimicrobial drug discovery.