Many persistent and chronic bacterial infections, including respiratory and urinary tract infections (UTIs), infections on medical devices and infections of the ear and heart, are associated with the formation of aggregates and biofilms that are difficult to treat. Thus, an increased understanding of the mechanisms employed by bacteria to form biofilms is essential for the development of strategies to combat these persistent and intrinsically resistant bacterial infections. One mechanism of bacterial aggregation and biofilm formation involves the expression of self-associating surface-located autotransporter (AT) proteins. Our work focuses on investigating the structural diversity of AT proteins to understand how these proteins self associate and promote those virulence phenotypes. We have recently elucidated the structure of Antigen 43 (Ag43), an AT protein from uropathogenic E. coli (UPEC). Our studies have shown how Ag43's L-shaped structure drives the formation of cell aggregates via a molecular Velcro-like mechanism where AT molecules in neighbouring cells self associate in a head to tail manner. Furthermore, our recent studies on other AT from E. coli pathotypes using biophysical and molecular approaches show an unexpected diversity in 3D structure and mechanism of association, which results in different virulence functions. In this presentation I will describe our latest results demonstrating the structural diversity in the AT family and how this dictates different protein-protein interactions that determine their specific biological activity. We are also developing specific inhibitors of these interactions to block AT function and inhibit bacterial aggregation and biofilm formation.
References:  Heras B, Totsika M, Peters KM, Paxman JJ, Gee CL, Jarrott RJ, Perugini MA, Whitten AE and Schembri MA (2014) The antigen 43 structure reveals a molecular Velcro-like mechanism of autotransporter-mediated bacterial clumping, Proc Natl Acad Sci USA 111, 457-462.