Sci Transl Med

. 2020 Nov 18;12(570):eabb3791.

doi: 10.1126/scitranslmed.abb3791.

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 ⁹

Affiliations expand

• PMID: 33208501

DOI: 10.1126/scitranslmed.abb3791

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.