Rescuing tetracycline class antibiotics for the treatment of multidrug resistant Acinetobacter baumannii pulmonary infection

Acinetobacter baumannii causes high mortality in ventilator-associated pneumonia patients and antibiotic treatment is compromised in multi-drug resistant strains resistant to ?-lactams, carbapenems, cephalosporins, polymyxins and tetracyclines. Among COVID-19 patients receiving ventilator support, multi-drug resistant A. baumannii secondary infection is associated with a two-fold increase in mortality. Here we investigated the use of the 8-hydroxyquinoline ionophore PBT2 to break resistance of A. baumannii to tetracycline class antibiotics. In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline or tigecycline was found to be bactericidal against multi-drug resistant A. baumannii, and resistance that did arise imposed a fitness cost. PBT2 and zinc disrupted heavy metal homeostasis in A. baumannii. Using a murine model, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multi-drug resistant A. baumannii pulmonary infection. PBT2 may find utility as a resistance breaker for treatment of high-priority multi-drug resistant pathogens.