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Jason Paxman

La Trobe Institute for Molecular Science, Australia

Title: Using protein crystallography to disarm bacterial pathogens

Biography

Jason Paxman is a senior postdoctoral researcher within the group led by Dr Begoña Heras within the Department of Biochemistry and Genetics at the La Trobe Institute for Molecular Science, Melbourne Australia. He has a strong interest in deciphering the mechanisms of action of bacterial virulence factors using X-ray crystallography. During his PhD at Monash University Australia he revealed for the first time how DsbA, a key bacterial virulence regulator, binds and folds a plethora of bacterial virulence factors. Past appointments include the Commonwealth Scientific and Industrial Research Organisation, The University of Melbourne and the Australian Synchrotron. Career highlights include developing anti-anthrax agents for the U.S. Department of Defence and being awarded an Australian Synchrotron Research Fellowship. His current work includes determining the mechanisms of action for one of the largest groups of bacterial virulence factors, the autotransporters.

Abstract

Emerging bacterial resistance to antibiotics was recently described by the World Health Organisation as a ‘global health emergency’. The development of new types of antibiotics is clearly not keeping pace with bacterial resistance. If we are to solve this problem we need alternative ways of thinking. We still know so little with regard to how bacteria use protein virulence factors to colonise, infect and cause diseases in hosts at the molecular level, and this information is pivotal towards developing new anti-microbials. My research involves understanding the molecular mechanisms of bacterial virulence factors and their regulators along with their roles in bacterial pathogenesis. I use various forms of recombinant protein expression, production and purification to produce these virulence factors for protein crystallisation. Utilising the Australian Synchrotron I then solve the structures of these virulence factors, and in combination with both biophysical and biochemical assays, I determine their mechanisms of action and then how to inhibit their functions. Autotransporter proteins are the largest group of outer membrane and secreted virulence factors from medically important bacterial pathogens. We were the first to reveal how autotransporter adhesins from pathogenic E. coli such as Antigen 43 promote biofilm formation while others such as UpaB can faciliate colonisation of human epithelium. Using this knowledge we have since developed inhibitors that can bind these adhesins to block their pathogenic phenotypes. Bacterial disulfide oxidoreductases are critical for the stable folding of many virulence factors. In this area we have well established research of targeting widespread disulfide oxidoreductases to inhibit the production of functional virulence factors. Overall, our research is leading the way towards developing anti-bacterial therapeutics that target the virulence factors themselves and so offer reduced emergence of bacterial resistance.