Covalent host targeting by thioester domains of Gram-positive pathogens

Lead Research Organisation: John Innes Centre
Department Name: Contracts Office

Abstract

We have identified a family of protein domains, containing internal thioester bonds, in many surface proteins of some of the most important Gram-positive human pathogens. Internal thioesters have previously only been found in complement proteins where they form covalent bonds to the surface of pathogens. The discovery of reactive thioester bonds in bacterial surface proteins known or predicted to mediate bacterial adhesion suggests the exciting possibility of a previously unrecognised principle in host-bacteria interactions, namely the covalent attachment of bacteria to host tissue.

We aim to study the role of protein domains that contain internal thioesters in bacterial adhesion using a range of in vitro and in vivo experiments including structural biology, protein/protein interactions, chemistry and cell-adhesion.

Given the urgent need to develop new antimicrobial strategies to prevent the looming antibiotics crisis, the discovery of a novel molecular virulence mechanism is an exciting development and needs to be addressed now in a concerted effort bringing together molecular and microbiological expertise as we propose.

Publications

10 25 50
 
Description Funded by an MRC grant linked to this BBSRC code, we showed that:

1. Thioester-containing domains are
unexpectedly prevalent in Gram-positive bacteria, including many clinically relevant pathogens.

2. TEDs comprise a conserved protein structure, despite having diverse protein sequence.

3. TEDs can mediate covalent cross-links to specific host cell surface proteins to mediate bacterial attachment.

4. Identification of an as yet unexploited target to treat bacterial infection and may also offer novel opportunities for engineering beneficial interactions.
Exploitation Route Others may seek to understand how our findings can be targetted for the development of novel anti-bacterials against cell adhesion in important mammalian diseases of Gram+ pathogens.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Collaboration with Lab of Schwarz-Linek in St Andrews, Scotland 
Organisation University of St Andrews
Country United Kingdom 
Sector Academic/University 
PI Contribution I was co-I on a successful MRC application including a full postdoc. The PI and myself worked closely through the project to ensure outcomes were met.
Collaborator Contribution PI (St Andrews) and myself worked closely through the research project to ensure outcomes were met.
Impact Published manuscripts as described under award CA506.
Start Year 2010