Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis
- 18 November 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (570)
- https://doi.org/10.1126/scitranslmed.abb3791
Abstract
The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum β-lactamase (ESBL)–producing bacteria is a critical threat to human health, and alternative treatment strategies are urgently required. We investigated the ability of the hydroxyquinoline analog ionophore PBT2 to restore antibiotic sensitivity in polymyxin-resistant, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 resensitized Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including the less toxic next-generation polymyxin derivative FADDI-287, in vitro. We were unable to select for mutants resistant to PBT2 + FADDI-287 in polymyxin-resistant E. coli containing a plasmid-borne mcr-1 gene or K. pneumoniae carrying a chromosomal mgrB mutation. Using a highly invasive K. pneumoniae strain engineered for polymyxin resistance through mgrB mutation, we successfully demonstrated the efficacy of PBT2 + polymyxin (colistin or FADDI-287) for the treatment of Gram-negative sepsis in immunocompetent mice. In comparison to polymyxin alone, the combination of PBT2 + polymyxin improved survival and reduced bacterial dissemination to the lungs and spleen of infected mice. These data present a treatment modality to break antibiotic resistance in high-priority polymyxin-resistant Gram-negative pathogens.Keywords
Funding Information
- National Health and Medical Research Council (GNT1176180)
- National Health and Medical Research Council (GNT1176180)
- National Health and Medical Research Council (GNT1176180)
- National Health and Medical Research Council (GNT1176180)
- National Health and Medical Research Council (GNT1071659)
- National Health and Medical Research Council (GNT1071659)
- National Health and Medical Research Council (GNT1194130)
- National Health and Medical Research Council (GNT1071659)
- Swiss National Science Foundation (P2ZHP3_191292)
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