Abstract
Nosocomial infections affect hundreds of millions of patients worldwide each year, and ~60% of these infections are associated with biofilm formation on an implanted medical device. Biofilms are dense communities of microorganisms in which cells associate with surfaces and each other using a self-produced extracellular matrix composed of proteins, polysaccharides, and genetic material. Proteins in the extracellular matrix take on a variety of forms, but here we focus on functional amyloid structures. Amyloids have long been associated with protein misfolding and neurodegenerative diseases, but recent research has demonstrated that numerous bacterial species utilize the amyloid fold to fortify the biofilm matrix and resist disassembly. Consequently, these functional amyloids, in particular the soluble oligomeric intermediates formed during amyloidogenesis, represent targets to destabilize the extracellular matrix and interrupt biofilm formation. Our previous studies suggested that these amyloidogenic intermediates adopt a non-standard structure, termed “α-sheet”, as they aggregate into soluble oligomeric species. This led to the design of complementary α-sheet peptides as anti-α-sheet inhibitors; these designs inhibit amyloidogenesis in three unrelated mammalian disease-associated systems through preferential binding of soluble oligomers. Here we show that these anti-α-sheet peptides inhibit amyloid formation in Staphylococcus aureus biofilms. Furthermore, they inhibit aggregation of pure, synthetic phenol soluble modulin α1, a major component of Staphylococcus aureus functional amyloids. As it aggregates phenol soluble modulin α1 adopts α-helix then α-sheet and finally forms β-sheet fibrils. The binding of the designed peptide inhibitors coincides with the formation of α-sheet.
Highlights
Nosocomial infections, or healthcare-associated infections, are the most common adverse event in healthcare delivery worldwide, leading to significant mortality and financial losses in a variety of settings
We begin with a short description of the α-sheet designs employed here and their spectral properties given the importance of structure in their mechanism of action, as well as what that suggests about the structure of amyloid species with which they interact
Fibril formation decreased in a dose-dependent manner when S. aureus MN8 biofilms were grown with increasing concentrations of AP90 in the culture medium (Fig. 1c)
Summary
Nosocomial infections, or healthcare-associated infections, are the most common adverse event in healthcare delivery worldwide, leading to significant mortality and financial losses in a variety of settings. In the United States in 2014, approximately one in 25 patients contracted at least one infection during the course of hospitalization, and the frequency of hospital-acquired infections in developing countries is expected to be at least three times higher than in the United States.[1, 2] This problem is compounded by the fact that ~60% of these infections are associated with biofilm formation.[3] Microbial infections occur within surgical wounds, as well as on most implanted medical devices, including prosthetic heart valves, pacemakers, cerebrospinal fluid shunts, urinary and intravascular catheters, ocular prostheses, and intrauterine contraceptive devices.[4] When microbes dwell on these surfaces within a biofilm, their susceptibility to antibiotics can decrease by a factor of 10–1000. Nine classes of antibacterial drugs were introduced between 1936 and 1968, but only five new classes have been approved since .[9]
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