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

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dc.contributor.authorDe Oliveira, D.M.P.
dc.contributor.authorBohlmann, L.
dc.contributor.authorConroy, T.
dc.contributor.authorJen, F.E.-C.
dc.contributor.authorEverest-Dass, A.
dc.contributor.authorHansford, K.A.
dc.contributor.authorBolisetti, R.
dc.contributor.authorEl-Deeb, I.M.
dc.contributor.authorForde, B.M.
dc.contributor.authorPhan, M.-D.
dc.contributor.authorLacey, J.A.
dc.contributor.authorTan, A.
dc.contributor.authorRivera-Hernandez, T.
dc.contributor.authorBrouwer, S.
dc.contributor.authorKeller, N.
dc.contributor.authorKidd, T.J.
dc.contributor.authorCork, A.J.
dc.contributor.authorBauer, M.J.
dc.contributor.authorCook, G.M.
dc.contributor.authorDavies, M.R.
dc.contributor.authoret al.
dc.date.issued2020
dc.description.abstractThe 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.
dc.description.statementofresponsibilityDavid M.P. De Oliveira, Lisa Bohlmann, Trent Conroy, Freda E.-C. Jen, Arun Everest-Dass, Karl A. Hansford, Raghu Bolisetti, Ibrahim M. El-Deeb, Brian M. Forde, Minh-Duy Phan, Jake A. Lacey, Aimee Tan, Tania Rivera-Hernandez, Stephan Brouwer, Nadia Keller, Timothy J. Kidd, Amanda J. Cork, Michelle J. Bauer, Gregory M. Cook, Mark R. Davies, Scott A. Beatson, David L. Paterson, Alastair G. McEwan, Jian Li, Mark A. Schembri, Mark A. T. Blaskovich, Michael P. Jennings, Christopher A. McDevitt, Mark von Itzstein, Mark J. Walker
dc.identifier.citationScience Translational Medicine, 2020; 12(570):eabb3791-1-eabb3791-10
dc.identifier.doi10.1126/scitranslmed.abb3791
dc.identifier.issn1946-6234
dc.identifier.issn1946-6242
dc.identifier.orcidMcDevitt, C.A. [0000-0003-1596-4841]
dc.identifier.urihttp://hdl.handle.net/2440/129861
dc.language.isoen
dc.publisherAmerican Association for the Advancement of Science
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1176180
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1071659
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1194130
dc.relation.grantARC
dc.rightsCopyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
dc.source.urihttps://doi.org/10.1126/scitranslmed.abb3791
dc.subjectAnimals
dc.subjectMice
dc.subjectBacteria
dc.subjectEscherichia coli
dc.subjectKlebsiella pneumoniae
dc.subjectSepsis
dc.subjectNeurodegenerative Diseases
dc.subjectColistin
dc.subjectEscherichia coli Proteins
dc.subjectPharmaceutical Preparations
dc.subjectAnti-Bacterial Agents
dc.subjectMicrobial Sensitivity Tests
dc.subjectDrug Resistance, Bacterial
dc.subjectDrug Resistance, Multiple, Bacterial
dc.subjectDrug Repositioning
dc.titleRepurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis
dc.typeJournal article
pubs.publication-statusPublished

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