In Gram-negative bacteria, the Autotransporters (ATs) are the largest group of outer membrane and secreted proteins. They promote a wide array of pathogenic phenotypes from many medically relevant bacterial pathogens. Each AT protein contains both the primary secretion machinery (translocator) for transport to the bacterial surface and the functional cargo (passenger) that directly contributes to disease [1]. The passenger domains display astounding functional diversity including host adhesion, bacterial aggregation/biofilm formation, invasion, intracellular motility, and immune evasion, along with enzymatic activities such as serine proteases, lipases, and sialidases that act as cytotoxins and in nutrient acquisition. Collectively, ATs contribute to a wide range of bacterial diseases, including whooping cough, urinary tract infections, nosocomial infections, diabetic ulcers, sepsis, and meningitidis.
Despite their abundance and important role in bacterial diseases, ATs are poorly understood and, until recently, there was no adequate classification system to describe the functional classes of the protein family. We addressed this by developing a phylogenetics-based classification system drawing on insights from our own research and the published literature. For the first time, all members of the AT family are classified into groups according their molecular structure and function [1].
This new classification provides new insights and information to further characterise AT protein mechanisms in disease. Using this system, we have directed our attention toward characterising relatively unknown ATs from the pathogen Bordetella pertussis (whooping cough). Using a combination of structural biology (Australian Synchrotron) along with other experimental techniques, we are uncovering the molecular mechanisms of these ATs and their role in promoting whooping cough. In other research, we have used our new AT classification system to identify AT functions for use in medical applications. Currently, I am re-purposing the AT toxins to create the first AT platform for the intracellular delivery of therapeutics into human tissue. Such a medical innovation would be highly beneficial to medicine, as 30% of all human therapeutics are peptide/protein based, which cannot cross human cell membranes.