POS-WED-067

Structure-function properties of novel FimH adhesins from multidrug resistant Escherichia coli ST131

L Nolan, S Sarkar, J Harris and M Totsika

Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Australia

Escherichia coli Sequence Type 131 (ST131) has recently emerged globally as a major cause of multidrug resistant urinary tract and bloodstream infections in hospitals and the community. FimH is a well-studied E. coli adhesin with a critical role in extra-intestinal pathogenesis and is a target for new therapies for urinary tract infections (UTIs). Previous studies on non-ST131 uropathogens have revealed that single amino acid changes outside the mannose binding pocket of FimH can have a significant effect on adhesin function. Here we examine novel FimH variants found in the majority of clinical ST131 isolates that have not been previously studied. Using sequence-based analyses and molecular dynamics (MD) we are investigating the effect of FimH sequence diversity on adhesin structure. Preliminary MD findings and structural comparisons of the three most dominant ST131 FimH variants suggest that amino acid mutations unique to ST131 can significantly alter the structural conformation of FimH and potentially its function. The most prevalent FimH type among clinical ST131 strains (FimH30) appears to allow for less interaction between its two domains when bound to mannose, suggesting that it adopts a more elongated conformation which is associated with a higher affinity for its natural ligand and may increase adhesion to bladder and intestinal cells. Adhesion and invasion findings support this hypothesis. This project aims to elucidate the unique structure-function properties of E. coli ST131 FimH variants, which may provide an explanation for the widespread success of this clinically important pandemic lineage. Our findings are expected to inform preclinical studies on novel oral FimH inhibitors that have been shown to inhibit ST131 adhesion.