Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/129861
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Type: Journal article
Title: Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis
Author: 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.
Citation: Science Translational Medicine, 2020; 12(570):eabb3791-1-eabb3791-10
Publisher: American Association for the Advancement of Science
Issue Date: 2020
ISSN: 1946-6234
1946-6242
Statement of
Responsibility: 
David 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
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.
Keywords: Animals
Mice
Bacteria
Escherichia coli
Klebsiella pneumoniae
Sepsis
Neurodegenerative Diseases
Colistin
Escherichia coli Proteins
Pharmaceutical Preparations
Anti-Bacterial Agents
Microbial Sensitivity Tests
Drug Resistance, Bacterial
Drug Resistance, Multiple, Bacterial
Drug Repositioning
Rights: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
DOI: 10.1126/scitranslmed.abb3791
Grant ID: http://purl.org/au-research/grants/nhmrc/GNT1176180
http://purl.org/au-research/grants/nhmrc/GNT1071659
http://purl.org/au-research/grants/nhmrc/GNT1194130
ARC
Appears in Collections:Aurora harvest 4
Microbiology and Immunology publications

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