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

Sci Transl Med. 2020 Nov 18;12(570):eabb3791. doi: 10.1126/scitranslmed.abb3791.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Bacteria
  • Colistin / pharmacology
  • Drug Repositioning
  • Drug Resistance, Bacterial
  • Drug Resistance, Multiple, Bacterial
  • Escherichia coli
  • Escherichia coli Proteins* / pharmacology
  • Klebsiella pneumoniae
  • Mice
  • Microbial Sensitivity Tests
  • Neurodegenerative Diseases*
  • Pharmaceutical Preparations*
  • Sepsis* / drug therapy


  • Anti-Bacterial Agents
  • Escherichia coli Proteins
  • MCR-1 protein, E coli
  • Pharmaceutical Preparations
  • Colistin