DsbA Foldases from Multidrug Resistant Pathogens as Targets for New Antimicrobials

Project dates: 01/04/2018 - 31/03/2021

In 2014 the World Health Organization declared antimicrobial resistance a global health priority. With 10 million deaths per year predicted by 2050 due to drug resistant infections, new therapies to tackle multidrug resistant pathogens need to be developed now. Drugs targeting bacterial virulence are a promising new class of antimicrobials hailed as evolutionary robust therapeutics for common bacterial infections. We have developed novel inhibitors of DsbA, a protein-folding enzyme (foldase) with a central role in pathogen virulence. In this project we will focus on two clinically important pathogens responsible for >200 million human infections globally pa: uropathogenic Escherichia coli (major cause of urinary tract infections and sepsis) and Salmonella enterica (major cause of foodborne diarrhoea). We have already shown that these pathogens possess multiple DsbA foldases that are structurally and functionally diverse. Here, using a combination of genetic, biophysical and structural methods, we will characterise the precise role of different DsbA foldases in E. coli urinary tract infection and Salmonella intestinal infection in vitro and in vivo. We will also evaluate the effect of our current crop of DsbA inhibitors against each of these diverse DsbA targets, their potential to attenuate pathogen virulence during infection, human cell toxicity and off-target effects. Overall, this project will generate critical new knowledge on new antimicrobial targets from pathogens of global public health significance and offer timely insight into the application of novel DsbA inhibitors as therapies for antibiotic resistant infections.

Read more about the Bacterial Pathogenesis Research group


Funding / Grants

  • National Health & Medical Research Council (NHMRC)

Team

Other Team Members

Partners

Other Partners

  • La Trobe University – La Trobe University
  • Griffith University – Griffith University (GU)

Dr Makrina Totsika is examining bacterial pathogenesis