Oral Presentation 11th Annual Conference of the International Chemical Biology Society 2022

Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria   (#17)

David MP De Oliveira 1 , Bernhard Keller 1 , Andrew Hayes 2 , Cheryl-lnn Ong 1 , Nichaela Harbison-Price 1 , Ibrahim M El-Deeb 3 , Gen (Tom) Li 1 , Nadia Keller 1 , Lisa Bohlmann 1 , Stephan Brouwer 1 , Andrew G Turner 1 , Amanda Cork 1 , Thomas Jones 4 , David Paterson 5 , Alastair McEwan 1 , Mark Davies 2 , Christopher McDevitt 2 , Mark von Itzstein 3 , Mark 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, The University of Queensland, Brisbane, QLD, Australia

Gram-positive bacteria do not produce lipopolysaccharide as a cell wall component. As such, the polymyxin class of 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 the lipopolysaccharide modification pathways that confer polymyxin resistance1. Here, in combination with zinc, PBT2 was shown to break intrinsic polymyxin resistance in Streptococcus pyogenes (Group A Streptococcus; GAS), Staphylococcus aureus (including methicillin-resistant S. 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 the 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 from which to investigate the utility of PBT2 and next-generation polymyxin antibiotics for the treatment of Gram-positive bacterial infections.

  1. De Oliveira D.M.P., et al. Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis. Sci. Transl. Med. 2020;12:eabb3791.