Abstract
Within intensive care units, multi-drug resistant Acinetobacter baumannii outbreaks are a frequent cause of ventilator-associated pneumonia. During the on-going COVID-19 pandemic, patients who receive ventilator support experience a 2-fold increased risk of mortality when they contract a secondary A. baumannii pulmonary infection. In our recent paper (De Oliveira et al. (2022), Mbio, doi: 10.1128/mbio.03517-21), we demonstrate that the 8-hydroxquinoline ionophore, PBT2 breaks 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 multi-drug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multi-drug resistant A. baumannii infections.
Highlights
The hydroxyquinoline ionophore, PBT2, was originally developed as a potential treatment for Alzheimer’s and Huntington’s disease, progressing to phase 2 human clinical trial with a favourable drug-safety profile
These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracyclineclass antibiotics commonly employed to treat multidrug resistant A. baumannii infections
It has been previously demonstrated that PBT2 mediated disruption to metal ion homeostasis enhances antibiotic sensitivity to polymyxin class antibiotics in otherwise resistant strains of multi-drug resistant (MDR) A. baumannii
Summary
The hydroxyquinoline ionophore, PBT2, was originally developed as a potential treatment for Alzheimer’s and Huntington’s disease, progressing to phase 2 human clinical trial with a favourable drug-safety profile. 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. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii.
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