Oral Presentation BACPATH 2022

Rescuing Tetracycline Class Antibiotics for the Treatment of Multidrug-Resistant Acinetobacter baumannii Pulmonary Infection (#23)

David De Oliveira 1 , Brian Forde 2 , Minh Duy Phan 1 , Bernhard Keller 1 , BIng Zhang 3 , Johannes Zuegg 3 , Ibrahim M El-deeb 4 , Gen (Tom) Li 1 , Nadia Keller 1 , Stephan Brouwer 1 , Nichaela Harbison-Price 1 , Amanda Cork 1 , Michelle Bauer 2 , Saleh Alquethamy 5 , Scott Beatson 1 , Jason A Roberts 2 , David L Paterson 2 , Alastair McEwan 1 , Mark Blaskovich 3 , Mark Schembri 1 , Christopher McDevitt 5 , Mark von Itzstein 4 , Mark Walker 1
  1. School of Chemistry and Molecular Biosciences, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
  2. The University of Queensland Centre for Clinical Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
  3. Centre for Superbug Solutions, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
  4. Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
  5. Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia

Acinetobacter baumannii causes high mortality in ventilator-associated pneumonia patients, and antibiotic treatment is compromised by multidrug-resistant strains resistant to β-lactams, carbapenems, cephalosporins, polymyxins, and tetracyclines. Among COVID-19 patients receiving ventilator support, a multidrug-resistant A. baumannii secondary infection is associated with a 2-fold increase in mortality. Here, we investigated the use of the 8-hydroxyquinoline ionophore PBT2 to break the resistance of A. baumannii to tetracycline class antibiotics. In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multidrug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. PBT2 and zinc disrupted metal ion homeostasis in A. baumannii, increasing cellular zinc and copper while decreasing magnesium accumulation. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii.1 These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multidrug-resistant A. baumannii infections.

  1. De Oliveira DMP, Forde BM, Phan MD, Steiner B, Zhang B, Zuegg J, El-Deeb IM, Li G, Keller N, Brouwer S et al: Rescuing Tetracycline Class Antibiotics for the Treatment of Multidrug-Resistant Acinetobacter baumannii Pulmonary Infection. mBio 2022:e0351721.