Oral Presentation BACPATH 2022

The molecular basis of how different strains and pathotypes of diarrhoeagenic and uropathogenic E.coli form biofilms on host surfaces. (#21)

Jason J Paxman 1 , Julieanne Vo 1 , Gabriella CM Ortiz 1 , Alvin W Lo 2 , Lilian Hor 1 , Makrina Totsika 3 , Mark Schembri 2 , Begoña Heras 1
  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
  2. Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
  3. Department of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia

Introduction:

Around 80% of human bacterial infections are associated with biofilms, where the aggregates of bacteria afford protection from host immune factors, removal by body peristalsis and antimicrobials. In fact the persistence of bacteria within biofilms is a leading cause for the worldwide and ever increasing threat of bacterial resistance to antibiotics. Here we reveal the molecular mechanisms of how non-fimbrial adhesins1 promote intimate biofilm formation on human epithelial surfaces by uropathogenic, enterohemorrhagic and entertoxigenic E. coli that are responsible for urinary tract and severe diarrheal infections.

Aims: We sought to progress from the multitude of genotype-phenotype studies to gain a molecular understanding of how non-fimbrial adhesins are involved in promoting biofilms on epithelial surfaces.

Methodology:

In conjunction with expert collaborators we have developed a program to study virulence factors such as the non-fimbrial adhesins using a multidisciplinary approach of using X-ray crystallography combined with biophysical, biochemical, cellular, microbiology and animal models of infection.

Findings:

Our research has shown how pathogenic bacteria such as E. coli use non-fimbrial adhesins to intimately adhere to host epithelial surfaces2. Now with another 6 crystal structures of these adhesins in combination with a plethora of functional data we show for the first time how pathogenic E. coli infections progress to forming persistent biofilms on epithelial surfaces3,4. Importantly we show how these large >500 residue bacterial surface adhesins promote biofilm formation through a loosely conserved 'handshake' mechanism. In addition, we reveal how processes such as the glycosylation of these adhesins can be used to switch bacteria from a biofilm phenotype to more active processes such as cellular invasion. But perhaps of even greater significance, we have used our molecular insights to develop and patent the first Australian inhibitor of medical bacterial biofilms5.

[1]Clarke...Paxman* and Heras*.(2022). Front. Immunol. [2]Paxman et al.,(2019). Nat. Commun. [3]Vo,..........Paxman* and Heras*(2022). Nature NPJ Biofilms Microbiomes. [4]Heras,..Paxman et al.,(2014). Proc Natl Acad Sci. [5]Heras, Paxman et al., PCT/AU2019/050893.