Oral Presentation Lorne Infection and Immunity 2021

Repurposing a neurodegenerative drug to treat Gram-negative antibiotic resistant bacterial infection (#22)

David MP De Oliveira 1 , Lisa Bohlmann 1 , Trent Conroy 2 , Freda E-C Jen 2 , Arun Everest-Dass 2 , Karl A Hansford 3 , Raghu Bolisetti 3 , Ibrahim M El-Deeb 2 , Brian M Forde 1 4 , Minh-Duy Phan 1 , Jake A Lacy 5 , Aimee Tan 5 , Tania Rivera-Hernandez 1 , Stephan Brouwer 1 , Nadia Keller 1 , Timothy J Kidd 1 , Amanda J Cork 1 , Michelle J Bauer 4 , Jason A Roberts 4 , Gregory M Cook 6 , Mark R Davies 5 , Scott A Beatson 1 , David L Paterson 4 , Alastair G McEwan 1 , Jian Li 7 , Mark A Schembri 1 , Mark A T Blaskovich 3 , Michael P Jennings 2 , Christopher A McDevitt 5 , Mark von Itzstein 2 , Mark J Walker 1
  1. Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia
  2. Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
  3. Centre for Superbug Solutions, Institute for Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia
  4. The University of Queensland Centre for Clinical Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
  5. Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia
  6. Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
  7. Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia

The continual emergence of multi- and extensively-drug resistant (MDR; XDR) bacteria is a critical threat to human health, and alternative treatment strategies are urgently required. PBT2 is an orally bioavailable hydroxyquinoline ionophore, which is able to mediate the transfer of metal ions such as zinc across biological membranes. PBT2 has progressed to phase 2 human clinical trials for the treatment of Huntington’s and Alzheimer’s diseases, with once-daily oral doses of 250 mg shown to be generally safe and well-tolerated when administered for periods of six to 24 months. Here, we investigated the ability of the ionophore PBT2 to restore antibiotic sensitivity in MDR and XDR, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 resensitised Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including the less toxic next-generation polymyxin derivative FADDI-287. PBT2 also resensitised several A. baumannii clinical isolates to the tetracycline class antibiotics -  tetracycline, tigecycline and minocycline. The mechanism of action responsible for these affects appear to be mediated through the dysregulation of bacterial metal homeostasis. Using a highly invasive K. pneumoniae strain engineered for polymyxin resistance through mgrB mutation, we successfully demonstrated the efficacy of PBT2 + polymyxin (colistin or FADDI-287) for the treatment of Gram-negative sepsis in immune-competent mice. Moreover, PBT2 mediated tetracycline resensitisation was also efficaciously demonstrated in vivo for the treatment of tetracycline-resistant A. baumannii pneumonia. In comparison to either polymyxin or tetracycline antibiotic alone, the combination of PBT2 with either polymyxin or tetracycline significantly improved survival and reduced the bacterial burden in the major organs of infected mice. These data present a treatment modality to break antibiotic resistance in high priority antimicrobial resistant Gram-negative pathogens.