Disordered bacterial proteins and their interactions with the human host

The global burden of the increasing number of severe bacterial and viral infections is a major concern.

One important pathogen causing such infections is the Streptococcus pyogenes bacterium, which ranks among the top ten causes of mortality from infectious diseases world-wide.

The focus here is on its poorly characterized intrinsically disordered virulence determinants, and their host interactions.

In this proposal we will push the frontier of the state-of the-art research in molecular infection medicine by applying a unique combination of methods in quantitative and structural mass spectrometry with integrative structural biology methods.

The overall purpose is to determine the genetic variation of these virulence determinants (Aim 1, 2023-2025); determine which host protein these target and how these complexes contribute to streptococcal pathogenesis (Aim 2, 2023-2026), and determine how these host-pathogen protein complexes are structured (Aims 3-4, 2023-2026).

This integrative approach will allow us to identify and depict druggable interfaces in unprecedented detail, with the future goal of screening for small molecule inhibitors or specific antibodies targeting these interfaces, as alternative therapies to traditional antibiotics.

Not only will the results obtained here be applicable to streptococcal infections, but more broadly to other pathogens as well, including novel, emerging viruses and zoonotic bacteria.