Abstract
Bacterial biofilms, especially those associated with implanted medical devices, are difficult to eradicate. Curli amyloid fibers are important components of the biofilms formed by the Enterobacteriaceae family. Here, we show that a human monoclonal antibody with pan-amyloid-binding activity (mAb 3H3) can disrupt biofilms formed by Salmonella enterica serovar Typhimurium in vitro and in vivo. The antibody disrupts the biofilm structure, enhancing biofilm eradication by antibiotics and immune cells. In mice, 3H3 injections allow antibiotic-mediated clearance of catheter-associated S. Typhimurium biofilms. Thus, monoclonal antibodies that bind a pan-amyloid epitope have potential to prevent or eradicate bacterial biofilms.
Highlights
IntroductionEspecially those associated with implanted medical devices, are difficult to eradicate
Bacterial biofilms, especially those associated with implanted medical devices, are difficult to eradicate
We show that 3H3 inhibits the polymerization of curli, leading to alteration of the biofilm architecture and rendering the biofilm bacteria more sensitive to antibiotic treatment and to macrophage uptake
Summary
Especially those associated with implanted medical devices, are difficult to eradicate. Biofilms form a physical barrier to many antibiotics, restricting effective drug concentrations to sub-lethal levels and promoting the outgrowth of resistant strains[20]. They block host immune responses, protecting cells from phagocytosis and complement mediated killing[21,22,23]. Curli promotes adhesion among bacteria within the biofilm and aids in surface attachment[35,36] Amyloids such as curli form insoluble protein polymers that are characterized by a repeated cross-beta-sheet structure that can display conformational antibody-binding epitopes shared by amyloids of completely unrelated protein sequences[37]. 3H3 is a human mAb that preferentially binds amyloid beta protein (Aβ) oligomers and fibrils, relative to Aβ monomers, as well as many types of pathologic human amyloids, including immunoglobulin light chain and transthyretin amyloids38. 3H3 inhibits polymerization of Aβ and other amyloid precursors in vitro and reduces amyloid deposition in transgenic mouse models of AD and familial Danish dementia
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