Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/129861
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
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 |
Published version: | http://dx.doi.org/10.1126/scitranslmed.abb3791 |
Appears in Collections: | Aurora harvest 4 Microbiology and Immunology publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.