Physical and molecular underpinnings of the multifunctionality of bacterial peptide assemblies

Introduction

An important challenge in biophysics is to understand the complex biological functions emerging from the physico-chemical properties of simple building blocks. Showcasing this challenging question is the multiple functions achieved by the phenol soluble modulins (PSMs) peptides from Staphylococcus aureus, able to self-assemble into amyloid structures, and underlying S. aureus pathogenicity.

Background

Over the past decade, the intrinsic capacity to form fibrils in vitro has been directly correlated with the peptide biological activities in vivo. This traditional focus severely limits our understanding of the role of more complex intermediate structures and dynamic interactions with the encountered biological membranes.

Objectives

Here, I propose to uncover the molecular determinants and mechanisms of self-assembly and its implication in dictating PSMs multifunctionality, from biofilm formation to inflammation and toxicity.

Hypothesis

I hypothesize that, beyond the current “one structure – one function” paradigm, intermediate assemblies are the membrane active entities and their co-aggregation with membrane components, such as lipids and proteins, contribute to their distinct functions.

Methodology

Building on my prior work on PSMα3 and my leading force in single-cell and single-molecule characterizations, I will:

1. Reveal the mechanism of self-assembly and the role of lipid co-factors.
2. Uncover the molecular modes of action of diverse assemblies at the membrane interface.
3. Establish in vivo how these assemblies drive host cell inflammation and death.
4. Explore the role of self-assembly in bacterial adhesion, in turn biofilm formation.

Expected Outcomes

By pinpointing the key characteristics of PSMs assemblies, from their physico-chemical to structural properties, responsible for their different functions, this project could set the basis for the design of novel structure-based therapeutics against staphylococcal infections, eliciting less antibio-resistance.