Virtual Poster 21st Lancefield International Symposium for Streptococci and Streptococcal Diseases 2022

Neurodegenerative disease treatment drug PBT2 breaks intrinsic polymyxin resistance in Gram-positive bacteria   (#417)

David MP De Oliveira 1 , Bernhard Keller 1 , Andrew J Hayes 2 , Cheryl-Lynn Y. Y Ong 1 , Nichaela Harbison-Price 1 , Ibrahim M El-Deeb 3 , Nadia Keller 1 , Lisa Bohlmann 1 , Stephan Brouwer 1 , Andrew G Turner 1 , Amanda J Cork 1 , Thomas R Jones 4 , David L Paterson 5 , Alastair G McEwan 1 , Mark R Davies 2 , Christopher A McDevitt 2 , Mark von Itzstein 3 , Mark J Walker 1
  1. School of Chemistry and Molecular Biosciences, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
  2. Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia
  3. Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
  4. School of Earth and Environmental Sciences, The University of Queensland, Brisbane, QLD, Australia
  5. The University of Queensland Centre for Clinical Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia

Gram-positive bacteria do not produce lipopolysaccharide as a cell wall component. As such, polymyxin class antibiotics which exert bactericidal activity against Gram-negative pathogens are ineffective against Gram-positive bacteria. The safe-for-human-use hydroxyquinoline analog ionophore PBT2 has been previously shown to break polymyxin resistance in Gram-negative bacteria, independent of lipopolysaccharide modification pathways that confer polymyxin resistance. Here, in combination with zinc, PBT2 was shown to break intrinsic polymyxin resistance in Streptococcus pyogenes (Group A Streptococcus; GAS), methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. Using the globally disseminated M1T1 GAS strain 5448 as a proof of principle model, colistin in the presence of PBT2 + zinc was shown to be bactericidal in activity. Any resistance that did arise imposed a substantial fitness cost. PBT2 + zinc dysregulated GAS metal ion homeostasis, notably decreasing cellular manganese content. Using a murine model of wound infection, PBT2 in combination with zinc and colistin proved an efficacious treatment against streptococcal skin infection. These findings provide a foundation to investigate the utility of PBT2 and next-generation polymyxin class antibiotics for the treatment of Gram-positive bacterial infections.