Staphylococcus aureus functional amyloids catalyze degradation of β-lactam antibiotics

Abstract

Antibiotic 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 (PSMs), functional bacterial amyloids secreted by Staphylococcus aureus, catalyze breakup of {beta}-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSM2 and, particularly, PSM3 catalyze hydrolysis of the amide-bond four-member ring of nitrocefin, a widely used {beta}-lactam surrogate. Microscopic and spectroscopic analyses of several PSM3 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- 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/526669v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@184141org.highwire.dtl.DTLVardef@643e8forg.highwire.dtl.DTLVardef@147488borg.highwire.dtl.DTLVardef@ebb7fa_HPS_FORMAT_FIGEXP M_FIG C_FIG