Invited Speaker Australian Society for Microbiology Annual Scientific Meeting 2023

Breakthroughs in understanding and combating bacterial biofilms (94005)

Jason J Paxman 1 , Lilian Hor 1 , Akila Pilapitiya 1 , Kaitlin Clarke 1 , Mark A Schembri 2 , Begoña Heras 1
  1. Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
  2. School of Chemistry and Molecular Biosciences , The University of Queensland, Brisbane, QLD 4072, Australia

Autotransporters are the largest family of surface bound and secreted proteins in Gram-negative bacteria, present in World Health Organization (WHO) listed critical high priority pathogens such as Escherichia coli, Serratia and Neisseria ssp. Autotransporter proteins facilitate multiple functions in bacterial infection, such as aggregation and biofilm formation,  host colonisation and invasion, along with tissue destruction and immunomodulation [1]. We are interested in understanding the molecular mechanisms underlaying how autotransporters contribute to bacterial pathogenesis. Using precision structural and molecular approaches we have shown that autotransporter adhesins like Ag43 adopt  a β-helical  structure and that head-to-tail interactions between Ag43 molecules in adjacent E. coli cells lead to bacterial clumping [2-4]. We have further demonstrated that this is a universally conserved mechanism for biofilm formation among  autotransporter adhesins. Our research also investigates secreted autotransporter toxins. We have recently revealed that the Ssp toxin from Serratia marcescens, displays   the common structural architecture for autotransporter toxins consisting of a protease "war head" attached to a β-helix stalk. However, the protease structural layout is unique amongst the many bacterial toxins that have been structurally characterised, and these idiosyncrasies are required for its cytotoxicity [5]. We are using the new fundamental knowledge on the autotransporter proteome  to develop inhibitory molecules that disarm rather than kill bacteria, such as our recently patented E. coli biofilm blocker [6].

  1. [1] Clarke, K. R. et al. Phylogenetic Classification and Functional Review of Autotransporters. Front Immunol 13, 921272, (2022).
  2. [2] Heras B. et al., The antigen 43 structure reveals a molecular Velcro-like mechanism of autotransporter-mediated bacterial clumping PNAS 111, 457-62 (2014).
  3. [3] Vo, J.L. et al., Variation of Antigen 43 self-association modulates bacterial compacting within aggregates and biofilms. npj Biofilms Microbiomes 8, 20 (2022).
  4. [4] Paxman, J.J. et al., Unique structural features of a bacterial autotransporter adhesin suggest mechanisms for interaction with host macromolecules. Nat Commun 10, 1967 (2019).
  5. [5] Hor, L. et al. Crystal structure of a subtilisin-like autotransporter passenger domain reveals insights into its cytotoxic function. Nat Commun, 14, 1163 (2023).
  6. [6] Heras B. et al., Compositions and methods for reducing bacterial aggregation. (2019) PCT/AU2019/050893.