Poster Presentation BacPath 2024

Exploring the utility of zinc-ionophores for the treatment of Acinetobacter baumannii lung infection (#57)

Ruby Heaton 1 , David MP De Oliveira 1 , Ibrahim M El-deeb 2 , Hayden Whyte 1 , Nia Bickham 1 , Gen (Tom) Li 1 , Olivia Bertolla 1 , Amanda J Cork 1 , Brian M Forde 1 , Maree T Smith 3 , Mark von Itzstein 2 , Mark J Walker 1
  1. Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
  2. Institute for Biomedicine and Glycomics, Griffith University, Gold Coast, QLD, Australia
  3. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia

Antimicrobial resistance (AMR) is a growing source of morbidity, mortality, and economic and health-care costs. In Australia, 9.9% of patients admitted to hospital will acquire an AMR-associated hospital-acquired infection resulting in 170,000 cases per year at an estimated economic burden of >$900 million annually. The innovative use of 8-hydroxyquinolone-containing ionophores to break antibiotic resistance in clinically relevant AMR-associated bacteria has paved a therapeutic pathway to investigate ionophores as direct-acting antibiotics and antibiotic potentiators. With transformational consequences for the future clinical management of AMR infections, we have synthesised a suite of 8-hydroxyquinolone containing novel chemical entities (NCEs) which demonstrate potent direct-antimicrobial efficacy and antibiotic resistance-breaking capacity against the nosocomial AMR-associated pathogen Acinetobacter baumannii; a World Health Organization priority pathogen frequently associated with central-line blood-stream infection and ventilator-associated pneumonia. As the 5th leading cause of death associated with AMR, A. baumannii infections are directly attributed to 123,000 deaths per year globally. The presence of carbapenem resistance directly attributes to >57,000 of these deaths (44%) respectively, surpassing carbapenem-resistance-attributed mortality rates observed during Escherichia coli (29,500 attributable deaths), Klebsiella pneumoniae (55,700 attributable deaths) and Pseudomonas aeruginosa (38,100 attributable deaths) infection. Mortality estimates for invasive CRAB infections exceeds 40%, in part due to the lack of effective treatment options. Here, we have generated proof-of-principle data with our lead NCE drug-candidates. For carbapenem-resistant A. baumannii (CRAB), our lead NCEs induce a bactericidal effect, permeabilise the bacterial outer-membrane, exhibit low resistance emergence properties, dysregulate bacterial zinc and iron metal-ion homeostasis, exhibit favorable toxicity profiles, and demonstrate both direct and antibiotic-potentiating therapeutic efficacy in vivo using a mouse model of A. baumannii lung infection. These NCEs represent a novel class of antibiotics and may serve to expand the repertoire of effective antibiotic therapies available for the treatment of CRAB infection.