Staphylococcus aureus functional amyloids catalyze degradation of β-lactam antibiotics

被引:11
作者
Arad, Elad [1 ,2 ]
Pedersen, Kasper B. [3 ]
Malka, Orit [2 ]
Mambram Kunnath, Sisira [1 ,2 ]
Golan, Nimrod [4 ]
Aibinder, Polina [5 ]
Schiott, Birgit [3 ,6 ]
Rapaport, Hanna [1 ,5 ]
Landau, Meytal [4 ,7 ,8 ]
Jelinek, Raz [1 ,2 ]
机构
[1] Ben Gurion Univ Negev, Ilse Katz Inst IKI Nanoscale Sci & Technol, IL-8410501 Beer Sheva, Israel
[2] Ben Gurion Univ Negev, Dept Chem, IL-8410501 Beer Sheva, Israel
[3] Aarhus Univ, Dept Chem, Langelandsgade 140, DK-8000 Aarhus C, Denmark
[4] Technion Israel Inst Technol, Dept Biol, IL-3200003 Haifa, Israel
[5] Ben Gurion Univ Negev, Avram & Stella Goldstein Goren Dept Biotechnol Eng, IL-8410501 Beer Sheva, Israel
[6] Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, Gustav Wieds Vej 14, DK-8000 Aarhus, Denmark
[7] Ctr Struct Syst Biol CSSB, D-22607 Hamburg, Germany
[8] European Mol Biol Lab EMBL, D-22607 Hamburg, Germany
关键词
SECONDARY STRUCTURE; RESISTANCE; PROTEIN; PEPTIDES; SIMULATIONS; ALPHA-3; DESIGN; GUI;
D O I
10.1038/s41467-023-43624-1
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 (PSM alpha s), functional bacterial amyloids secreted by Staphylococcus aureus, catalyze hydrolysis of beta-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSM alpha 2 and, particularly, PSM alpha 3 catalyze hydrolysis of the amide-like bond of the four membered beta-lactam ring of nitrocefin, an antibiotic beta-lactam surrogate. Examination of the catalytic activities of several PSM alpha 3 variants allowed mapping of the active sites on the amyloid fibrils' surface, specifically underscoring the key roles of the cross-alpha fibril organization, and the combined electrostatic and nucleophilic functions of the lysine arrays. Molecular dynamics simulations further illuminate the structural features of beta-lactam association upon the fibril surface. Complementary experimental data underscore the generality of the functional amyloid-mediated catalytic phenomenon, demonstrating hydrolysis of clinically employed beta-lactams by PSM alpha 3 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 beta-lactam antibiotics, underlying possible antibiotic resistance mechanisms associated with bacterial biofilms.
引用
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页数:15
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