Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis

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 res...

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Bibliographic Details
Published in:Science translational medicine 2020-11, Vol.12 (570)
Main Authors: De Oliveira, David M P, Bohlmann, Lisa, Conroy, Trent, Jen, Freda E-C, Everest-Dass, Arun, Hansford, Karl A, Bolisetti, Raghu, El-Deeb, Ibrahim M, Forde, Brian M, Phan, Minh-Duy, Lacey, Jake A, Tan, Aimee, Rivera-Hernandez, Tania, Brouwer, Stephan, Keller, Nadia, Kidd, Timothy J, Cork, Amanda J, Bauer, Michelle J, Cook, Gregory M, Davies, Mark R, Beatson, Scott A, Paterson, David L, McEwan, Alastair G, Li, Jian, Schembri, Mark A, Blaskovich, Mark A T, Jennings, Michael P, McDevitt, Christopher A, von Itzstein, Mark, Walker, Mark J
Format: Article
Language:English
Subjects:
Antibiotic resistance
Antibiotics
Colistin
Klebsiella pneumoniae
Mutation
Neurodegenerative diseases
Pathogens
Sepsis
Spleen
β Lactamase
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Summary: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 , , , and 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 containing a plasmid-borne gene or carrying a chromosomal mutation. Using a highly invasive strain engineered for polymyxin resistance through 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.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/SCITRANSLMED.ABB3791