Staphylococcus aureus functional amyloids catalyze degradation of β-lactam antibiotics

• Published in: Nature communications Vol. 14; no. 1; p. 8198
• Main Authors: Arad, Elad, Pedersen, Kasper B., Malka, Orit, Mambram Kunnath, Sisira, Golan, Nimrod, Aibinder, Polina, Schiøtt, Birgit, Rapaport, Hanna, Landau, Meytal, Jelinek, Raz
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.12.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 101/58; 119/118; 147/143; 631/326/421; 631/326/46; 639/638/45/603; Amides; Antibiotic resistance; Antibiotics; Bacteria; Biofilms; Degradation; Drug resistance; Fibrils; Humanities and Social Sciences; Hydrolysis; Lysine; Molecular dynamics; multidisciplinary; Phenols; Science; Science (multidisciplinary); Staphylococcus aureus; β-Lactam antibiotics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-43624-1

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 (PSMαs), functional bacterial amyloids secreted by Staphylococcus aureus , catalyze hydrolysis of β-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSMα2 and, particularly, PSMα3 catalyze hydrolysis of the amide-like bond of the four membered β-lactam ring of nitrocefin, an antibiotic β-lactam surrogate. Examination of the catalytic activities of several PSMα3 variants allowed mapping of the active 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 arrays. Molecular dynamics simulations further illuminate the structural features of β-lactam association upon the fibril surface. Complementary experimental data underscore the generality of the functional amyloid-mediated catalytic phenomenon, demonstrating hydrolysis of clinically employed β-lactams by PSMα3 fibrils, and illustrating antibiotic degradation in actual S. aureus biofilms and live bacteria environments. Overall, this study unveils functional amyloids as catalytic agents inducing degradation of β-lactam antibiotics, underlying possible antibiotic resistance mechanisms associated with bacterial biofilms. A number of mechanisms are known to mediate bacterial antibiotic resistance. Here, Arad et al show that amyloid fibrils produced by Staphylococcus aureus rapidly degrade common antibiotic molecules.