Acinetobacter baumannii is a significant nosocomial pathogen, frequently associated with high morbidity and mortality rates, and significant economic burden. Carbapenem-resistant A. baumannii (CRAB) infections are especially challenging and are identified as a critical pathogen on the World Health Organization’s 2024 priority pathogens list. Mortality estimates for severe CRAB infections exceed 40%, in part due to the lack of effective treatment options. For these infections, antibiotic treatment regimens encompassing β-lactams, carbapenems, cephalosporins, polymyxins, and tetracyclines are no longer effective.
Here, we investigated the use of the 8-hydroxyquinoline ionophore PBT2, to break the resistance of CRAB to tetracycline class antibiotics. In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against CRAB, and any resistance that did arise imposed a fitness cost. PBT2 and zinc disrupted metal ion homeostasis in CRAB, 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 tetracycline and tigecycline-resistant CRAB infection. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics during severe CRAB infections.