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• W2957845089 abstract "Anthrax is an ancient and deadly disease caused by the spore-forming bacterial pathogen Bacillus anthracis. At present, anthrax mostly affects wildlife and livestock, although it remains a concern for human public health—primarily for people who handle contaminated animal products and as a bioterrorism threat due to the high resilience of spores, a high fatality rate of cases and the lack of a civilian vaccination programme1,2. The cell surface of B. anthracis is covered by a protective paracrystalline monolayer—known as surface layer or S-layer—that is composed of the S-layer proteins Sap or EA1. Here, we generate nanobodies to inhibit the self-assembly of Sap, determine the structure of the Sap S-layer assembly domain (SapAD) and show that the disintegration of the S-layer attenuates the growth of B. anthracis and the pathology of anthrax in vivo. SapAD comprises six β-sandwich domains that fold and support the formation of S-layers independently of calcium. Sap-inhibitory nanobodies prevented the assembly of Sap and depolymerized existing Sap S-layers in vitro. In vivo, nanobody-mediated disruption of the Sap S-layer resulted in severe morphological defects and attenuated bacterial growth. Subcutaneous delivery of Sap inhibitory nanobodies cleared B. anthracis infection and prevented lethality in a mouse model of anthrax disease. These findings highlight disruption of S-layer integrity as a mechanism that has therapeutic potential in S-layer-carrying pathogens. The use of nanobodies that inhibit the self-assembly of the S-layer protein Sap from B. anthracis enabled the elucidation of the structure of this protein. The nanobodies also trigger disintegration of assembled S-layers and attenuate both bacterial growth and anthrax pathology in animal models of infection." @default.
• W2957845089 created "2019-07-23" @default.
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• W2957845089 date "2019-07-15" @default.
• W2957845089 modified "2023-10-16" @default.
• W2957845089 title "Structure of S-layer protein Sap reveals a mechanism for therapeutic intervention in anthrax" @default.
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• W2957845089 doi "https://doi.org/10.1038/s41564-019-0499-1" @default.
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• W2957845089 hasPublicationYear "2019" @default.
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