Research ArticleANTIBIOTIC RESISTANCE

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

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Science Translational Medicine  18 Nov 2020:
Vol. 12, Issue 570, eabb3791
DOI: 10.1126/scitranslmed.abb3791

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PBT2 pumps up polymyxins

Bacterial resistance to antibiotics is a growing worldwide problem, and Enterobacterales with resistance to the polymyxin class of antibiotics are a critical threat. De Oliveira et al. repurposed a hydroxyquinoline compound called PBT2, which has undergone phase 2 clinical trials for neurodegenerative diseases, to break polymyxin antibiotic resistance in four different Gram-negative pathogens, including Klebsiella pneumoniae and Pseudomonas aeruginosa. In vitro, treatment with PBT2 disrupted the abundance of zinc and iron in the resistant bacteria, whereas in immunocompetent septic mice, PBT2 combined with polymyxins resulted in improved survival with reduced bacterial dissemination. These findings, while exciting, are still to be confirmed in humans.

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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