Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis
David M P De Oliveira 1, Lisa Bohlmann 1, Trent Conroy 2, Freda E-C Jen 2, Arun Everest-Dass 2, Karl A Hansford 3, Raghu Bolisetti 3, Ibrahim M El-Deeb 2, Brian M Forde 1 4, Minh-Duy Phan 1, Jake A Lacey 5, Aimee Tan 5, Tania Rivera-Hernandez 1 6, Stephan Brouwer 1, Nadia Keller 1, Timothy J Kidd 1, Amanda J Cork 1, Michelle J Bauer 4, Gregory M Cook 7, Mark R Davies 5, Scott A Beatson 1, David L Paterson 4, Alastair G McEwan 1, Jian Li 8, Mark A Schembri 1, Mark A T Blaskovich 3, Michael P Jennings 2, Christopher A McDevitt 5, Mark von Itzstein 2, Mark J Walker 9AffiliationsDOI: 10.1126/scitranslmed.abb3791
- PMID: 33208501
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.
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