De Oliveira, D.M.P.Bohlmann, L.Conroy, T.Jen, F.E.-C.Everest-Dass, A.Hansford, K.A.Bolisetti, R.El-Deeb, I.M.Forde, B.M.Phan, M.-D.Lacey, J.A.Tan, A.Rivera-Hernandez, T.Brouwer, S.Keller, N.Kidd, T.J.Cork, A.J.Bauer, M.J.Cook, G.M.Davies, M.R.et al.2021-03-032021-03-032020Science Translational Medicine, 2020; 12(570):eabb3791-1-eabb3791-101946-62341946-6242http://hdl.handle.net/2440/129861The 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.enCopyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government WorksAnimalsMiceBacteriaEscherichia coliKlebsiella pneumoniaeSepsisNeurodegenerative DiseasesColistinEscherichia coli ProteinsPharmaceutical PreparationsAnti-Bacterial AgentsMicrobial Sensitivity TestsDrug Resistance, BacterialDrug Resistance, Multiple, BacterialDrug RepositioningJournal article100003068610.1126/scitranslmed.abb37910005919271000042-s2.0-85096407452557575McDevitt, C.A. [0000-0003-1596-4841]