Introduction:
Autotransporters are the largest and most widespread group of bacterial surface and secreted proteins. They are used to promote important pathogenic functions such as colonisation, biofilm formation, invasion and tissue destruction. However, very little is known with regard to the structures and functions of these proteins. Understanding the molecular details of how these proteins function is key to better understanding bacterial infections from diverse pathogens and will provide critical information that can be used to target these proteins for the development of new antimicrobials.
Aims:
We sought to uncover the structures, mode of action, regulation and roles in bacterial pathogenesis of autotransporters, and then to use this information to develop new inhibitors and other medical tools.
Methodology:
We combined a multidisciplinary approach of X-ray crystallography with biophysical, biochemical, cellular and microbiology methods.
Results:
Our findings show that the crystal structures of autotransporters reveal that these proteins form long β-helices that incorporate different features to allow binding and action on their target proteins. This common β-helix based domain allows for (i) direct binding to host epithelia to promote bacterial colonisation1 (ii) the formation of self-associations to create protective biofilms2 (iii) switching of binding modes to mediate bacterial invasion (iv) intracellular degradation of host tissue (v) and the ability to interact with both host and bacterial proteins to modulate infection and immune processes.
Conclusions:
We are now finally uncovering for the first time the roles, mechanisms and structures of this large and uncharacterised group of bacterial proteins. We can now appreciate in molecular detail how these autotransporters promote various types of bacterial infection processes. We are now using these findings to develop new types of antimicrobials and other medical tools3.