Science translational medicine · 2020
Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.