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. 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 against the nosocomial AMR-associated pathogen Acinetobacter baumannii; a World Health Organization priority pathogen frequently associated with blood, urinary tract, wound and lung infections. Here, we have generated proof-of-principle data with our lead NCE drug-candidates. For carbapenem-resistant strains of A. baumannii, the 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 favourable pharmacokinetic and toxicity profiles, and demonstrate 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 carbapenem-resistant A. baumannii infection.