Oral Presentation BacPath 13: Molecular Analysis of Bacterial Pathogens Conference 2015

Foldases from multidrug resistant pathogens as targets for antivirulence therapies (#39)

Makrina Totsika 1 , Luke Adams 2 , Mark Schembri 3 , Jennifer Martin 3 , Begoña Heras 4 , Martin Scanlon 2
  1. Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Kelvin Grove, QLD, Australia
  2. Department of Microbiology, Monash University, Clayton, VIC, Australia
  3. University of Queensland, St Lucia, QLD, Australia
  4. Biochemistry, La Trobe University, Melbourne, VIC, Australia

In April 2014, the World Health Organization declared antimicrobial resistance a public health priority demanding global action. Two million people are affected each year by antibiotic resistant infections in the US alone, resulting in 23,000 deaths, >$20 billion in health care costs and $35 billion in loss of productivity. If no action is taken, it is predicted that by 2050 common infections by multidrug resistant (MDR) pathogens, such as urinary tract infections and foodborne diarrhoea, will kill 10 million people each year; more than cancer. With few new drugs coming to market, there is an urgent need for new therapeutics to replace failing antibiotics. Unlike traditional antibiotics, antivirulence drugs inhibit bacterial virulence instead of growth offering a new class of ‘evolution-proof’ therapeutic. We have recently identified novel small molecule inhibitors of the prototypical DsbA from Escherichia coli.DsbA is a protein-folding enzyme (foldase) that catalyses the formation of disulfide bonds in secreted and outer membrane proteins in bacteria. As such, DsbA is a major facilitator of virulence in pathogens, as it is required to correctly fold key virulence factors, which are mainly cell surface or secreted proteins. In fact, many important pathogens, such as uropathogenic E. coli (UPEC) and Salmonella enterica serovar Typhimurium (S. Typhimurium), encode multiple DsbA homologues in their genome. Here we provide important proof-of-principle that our novel compounds can inhibit DsbA foldases in MDR pathogens reducing their virulence in vitro and that loss of DsbA reduces infection in vivo. Taken together, our findings suggest that targeting DsbA is a promising antivirulence strategy offering exciting support for further developing our lead inhibitors into novel antivirulence drugs.