Poster Presentation 16th Lorne Infection and Immunity 2026

Taking Bacterial Autotransporters from Pathogenic to Therapeutic (132568)

Kait Clarke 1 , Jason Paxman 1 , Begoña Heras 1
  1. Biochemistry and Chemistry, La Trobe University, Bundoora, VIC, Australia

Autotransporters (ATs) are bacterial nanomachines that drive virulence through diverse mechanisms including immune evasion, adhesion, and biofilm formation [1-4]. Evolving alongside us for millennia, ATs represent a versatile molecular toolkit that bacteria use to manipulate human biology. Although widespread across many pathogens, functional studies have largely focused on Escherichia coli, leaving many ATs from clinically relevant species unexplored [4]. This project both exploits the wealth of accumulated knowledge for well-characterised ATs and uncovers new mechanisms for poorly characterised ATs.

Our multidisciplinary approach spans structural biology, biophysics, cell biology, and microbiology to both understand and exploit the molecular mechanisms by which ATs contribute to pathogenesis. First, we exploit the extensive knowledge of E. coli ATs to engineer the protein Pet for intracellular drug delivery. Second, we investigate under-characterised ATs from Bordetella pertussis, the causative agent of whooping cough.

We have reprogrammed Pet to deliver therapeutic peptides into epithelial cells, triggering targeted, cargo-dependent cell death. This proof of principle will lead the way into using this platform to deliver other peptide drugs, increasing their efficacy by delivering them directly into the cytoplasm. 

 

References:

  1. Heras, B. et al. The antigen 43 structure reveals a molecular Velcro-like mechanism of autotransporter-mediated bacterial clumping. Proc Natl Acad Sci USA 111, 457-462, doi:10.1073/pnas.1311592111 (2014).
  2. Paxman, J. J. et al. Unique structural features of a bacterial autotransporter adhesin suggest mechanisms for interaction with host macromolecules. Nat Commun 10, 1967, doi:10.1038/s41467-019-09814-6 (2019)
  3. Vo, J. L. et al. Autotransporter adhesins in Escherichia coli pathogenesis. Proteomics 17, 1600431, doi:10.1002/pmic.201600431 (2017).
  4. Clarke KR, et al. Phylogenetic Classification and Functional Review of Autotransporters. Front. Immunol., doi:10.3389/fimmu.2022.921272 (2022).