PSMNano · Probing the fibrillation of Staphylococcal amyloids and their interactions with Membranes at the Nanoscale

Phenol-soluble modulins α3 (PSMα3) are functional amyloids involved in the virulence of Staphylococcus aureus, a multi-drug resistant pathogen under the surveillance of the European Union (EU). The project PSMNano aims at unveiling the molecular mechanisms driving PSMα3 interactions with cell membranes, which lead to their cytotoxic and proinflammatory activities, with a focus on the impact of amyloid fibrillation. So far poorly known, dissecting those mechanisms is yet critical to efficiently target PSMα3 activities, in turn S. aureus pathogenicity, and avoid the pandemics foreseen by the EU in the coming decades. Thanks to atomic force microscopy coupled to complementary multiscale biophysical tools, PSMNano will provide high spatiotemporal resolution multiparametric imaging of those interactions, while quantifying their affinity and energetic landscape, on both mimetic models and living cells. Remarkably, single-molecule experiments and cell budding will help decipher the forces driving the FPR2 receptor-dependent role of PSMα3. The expertise of the fellow Dr. Mathelié-Guinlet in surface chemistry and nanobiophysics related to bacterial virulence, the complementary knowledge she will acquire from the supervisor Pr. Molinari on membrane models design and spectroscopic investigations of amyloids, and the cutting-edge technical platforms of the host institution, CBMN (University of Bordeaux, France) will be instrumental for the success of this interdisciplinary project. The fundamental insights brought by the understanding of the role of PSMs-cell membrane interactions in S. aureus pathogenesis could set the stage for the design of novel therapeutics, e.g. inhibitors of PSMα3 activity. PSMNano could also open up avenues for standardized protocols to characterize amyloid-membrane interactions, involved in degenerative diseases. With valuable short- and long-term outcomes, this project will undoubtedly strengthen the competitiveness of the EU health program.