1. Engineering Chirally Blind Protein Pseudocapsids into Antibacterial Persisters
- Author
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Maxim G. Ryadnov, Smita B. Gunnoo, Franca Fraternali, Xiaoliang Ba, Mark A. Holmes, Emiliana De Santis, Helen Lewis, Ibolya E. Kepiro, Michael Shaw, Katharine Hammond, Urszula Łapińska, Stefano Pagliara, Irene Marzuoli, Bart W. Hoogenboom, Christian D. Lorenz, Kepiro, Ibolya E [0000-0002-8934-3389], Marzuoli, Irene [0000-0001-7536-6144], Hammond, Katharine [0000-0002-3755-6489], Ba, Xiaoliang [0000-0002-3882-3585], Lewis, Helen [0000-0002-9993-0640], Shaw, Michael [0000-0001-6099-3217], Gunnoo, Smita B [0000-0002-7435-8377], De Santis, Emiliana [0000-0002-0943-6586], Łapińska, Urszula [0000-0003-3593-9248], Pagliara, Stefano [0000-0001-9796-1956], Holmes, Mark A [0000-0002-5454-1625], Lorenz, Christian D [0000-0003-1028-4804], Hoogenboom, Bart W [0000-0002-8882-4324], Fraternali, Franca [0000-0002-3143-6574], Ryadnov, Maxim G [0000-0003-4847-1154], and Apollo - University of Cambridge Repository
- Subjects
Models, Molecular ,Protein Folding ,Multidrug tolerance ,medicine.drug_class ,Cell Survival ,Surface Properties ,Antibiotics ,Protein design ,nanopores ,General Physics and Astronomy ,02 engineering and technology ,Microbial Sensitivity Tests ,010402 general chemistry ,Protein Engineering ,01 natural sciences ,Broad spectrum ,Acquired resistance ,Antibiotic resistance ,medicine ,Escherichia coli ,General Materials Science ,antimicrobial resistance ,Particle Size ,protein design ,artificial pseudocapsids ,Chemistry ,General Engineering ,021001 nanoscience & nanotechnology ,Antimicrobial ,0104 chemical sciences ,Anti-Bacterial Agents ,superbugs ,persister cells ,Biophysics ,0210 nano-technology ,Antimicrobial Cationic Peptides - Abstract
Antimicrobial resistance stimulates the search for antimicrobial forms that may be less subject to acquired resistance. Here we report a conceptual design of protein pseudocapsids exhibiting a broad spectrum of antimicrobial activities. Unlike conventional antibiotics, these agents are effective against phenotypic bacterial variants, while clearing "superbugs" in vivo without toxicity. The design adopts an icosahedral architecture that is polymorphic in size, but not in shape, and that is available in both l and d epimeric forms. Using a combination of nanoscale and single-cell imaging we demonstrate that such pseudocapsids inflict rapid and irreparable damage to bacterial cells. In phospholipid membranes they rapidly convert into nanopores, which remain confined to the binding positions of individual pseudocapsids. This mechanism ensures precisely delivered influxes of high antimicrobial doses, rendering the design a versatile platform for engineering structurally diverse and functionally persistent antimicrobial agents.
- Published
- 2020