Staphylococcus aureusfunctional amyloids catalyze degradation of β-lactam antibiotics

Abstract

ABSTRACTAntibiotic resistance of bacteria is considered one of the most alarming developments in modern medicine. While varied pathways for bacteria acquiring antibiotic resistance have been identified, there still are open questions concerning the mechanisms underlying resistance. Here, we show that alpha phenol-soluble modulins (PSMα’s), functional bacterial amyloids secreted byStaphylococcus aureus, catalyze breakup of β-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSMα2 and, particularly, PSMα3 catalyze hydrolysis of the amide-bond four-member ring of nitrocefin, a widely used β-lactam surrogate. Microscopic and spectroscopic analyses of several PSMα3 variants and correlation with their catalytic activities allowed mapping of the catalytic sites on the amyloid fibrils’ surface, specifically underscoring the key roles of the cross-α fibril organization, and the combined electrostatic and nucleophilic functions of the lysine residue array. This study unveils a previously unknown role of functional bacterial amyloids as catalytic agents for antibiotic compounds, pointing to possible mechanisms for antibiotic resistance of bacteria.ToC Graphical Abstract