Designing a new molecule to target biofilm amyloids

Amyloids in the Staphylococcus aureus biofilm provide a lot of stability as well as many other virulence properties. A Seattle team is addressing the problem.

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Jul 12, 2017
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Phenol soluble modulins (PSMs) are versatile amyloids in S. aureus. They have a number of virulence properties, most notably killing human neutrophils. The also kill competing bacteria allowing S. aureus to thrive in niches around the human body where they can cause harm.

Importantly for us at NPJ Biofilms and Microbiomes, PSMs also have an important role in the S. aureus biofilm. They can promote biofilm dissociation which is a huge problem in the hospital as well as giving strength and rigidity to the biofilms when they are incorporated into the extracellular matrix. 

A research team in Seattle, Washington saw an opportunity to target PSMs in order to reduce the effectiveness of the S. aureus biofilm. They designed a peptide that can interact with the S. aureus PSMs and stop them from forming aggregates. The team showed that addition of their synthetic peptide, named AP90 reduced biofilm formation by preventing the aggregation of PSMs.


Designed α-sheet peptides suppress amyloid formation in Staphylococcus aureus biofilms

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.

Reference

Designed α-sheet peptides suppress amyloid formation in Staphylococcus aureus biofilms
Alissa Bleem, Robyn Francisco, James D. Bryers & Valerie Daggett.
npj Biofilms and Microbiomes 3, Article number: 16 (2017)
doi:10.1038/s41522-017-0025-2

Go to the profile of Ben Libberton

Ben Libberton

Communications Officer, MAX IV Laboratory

I'm a Communications Officer at MAX IV Laboratory in Lund, Sweden and the Community Editor for npj Biofilms and Microbiomes. I'm interested in how bacteria cause disease and look to technology to produce novel tools to study and ultimately prevent infection. Part of my current role is to find ways to use synchrotron radiation to study microorganisms.

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