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

    Author(s)
    De Oliveira, David MP
    Bohlmann, Lisa
    Conroy, Trent
    Jen, Freda E-C
    Everest-Dass, Arun
    Hansford, Karl A
    Bolisetti, Raghu
    El-Deeb, Ibrahim M
    Forde, Brian M
    Minh-Duy, Phan
    Lacey, Jake A
    Tan, Aimee
    Jennings, Michael P
    von Itzstein, Mark
    et al.
    Griffith University Author(s)
    Everest-Dass, Arun
    El-Deeb, Ibrahim Mustafa
    von Itzstein, Mark
    Jennings, Michael P.
    Jen, Freda E.
    Year published
    2020
    Metadata
    Show full item record
    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 ...
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    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.
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    Journal Title
    Science Translational Medicine
    Volume
    12
    Issue
    570
    DOI
    https://doi.org/10.1126/scitranslmed.abb3791
    Subject
    Clinical Sciences
    Microbiology
    Biological Sciences
    Medical and Health Sciences
    Science & Technology
    Life Sciences & Biomedicine
    Cell Biology
    Medicine, Research & Experimental
    Research & Experimental Medicine
    Publication URI
    http://hdl.handle.net/10072/400806
    Collection
    • Journal articles

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