Poster Presentation BACPATH 2022

Host-dependent resistance of Group A Streptococcus to antifolate antibiotics (#178)

Kalindu D Rodrigo 1 , Aarti Saiganesh 1 , Andrew J Hayes 2 , Jack Anstey 1 , Jua Iwasaki 1 , Janessa L Pickering 1 , Jessica Hillas 1 , Scott Winslow 1 , Tabitha Woodman 1 , Jake A Lacey 3 , Mark P. G. van der Linden 4 , Philip M Giffard 5 6 , Steven Y. C. Tong 3 7 , Keith A Stubbs 8 , Jonathan R Carapetis 1 9 , Asha C Bowen 1 9 , Mark R Davies 10 , Tim Barnett 1 11
  1. Wesfarmers Centre for Vaccines and Infectious Diseases, The Kids Research Institute Australia, Nedlands, WA, Australia
  2. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  3. Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  4. German National Reference Center for Streptococci, Institute of Medical Microbiology, , University Hospital RWTH Aachen, Aachen, Germany
  5. Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia
  6. College of Health and Human Sciences, Charles Darwin University, Darwin, NT, Australia
  7. Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  8. School of Molecular Sciences, University of Western Australia, Nedlands, WA, Australia
  9. Department of Infectious Diseases, Perth Children’s Hospital, Nedlands, WA, Australia
  10. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  11. School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia

Antimicrobial resistance (AMR) is a major threat to global human health. Improved AMR surveillance is one of several priorities identified by the World Health Organization to mitigate the burden of AMR and improve the use of existing antibiotics. Complicating surveillance is the fact that existing AMR genes do not explain all antibiotic-resistant infections. Using a combination of forced evolution and metabolic rescue experiments, we have identified a novel mechanism of resistance to sulfamethoxazole (a potent inhibitor of folate biosynthesis) in the major human pathogen Group A Streptococcus (GAS).  Resistance is mediated by a substrate-binding protein (ThfT) that expands the substrate profile of an endogenous ABC transporter to include multiple end products of the folate biosynthesis pathway. As this mechanism of AMR involves acquisition of these metabolites directly from the host it remains undetectable by in vitro antibiotic susceptibility testing methods. We propose that ThfT-mediated sulfamethoxazole resistance constitutes a new paradigm of bacterial AMR that is only active during an infection, and highlights the need to understand the activity of antibiotics in the context of the infections they are designed to treat. In this presentation, I will outline our recent data that has characterised this new mechanism of antibiotic resistance, and how we are now using this research to improve the treatment and prevention of GAS infections in remote Aboriginal and Torres Strait Islander communities.