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dc.contributor.authorDe Oliveira, David MP
dc.contributor.authorBohlmann, Lisa
dc.contributor.authorConroy, Trent
dc.contributor.authorJen, Freda E-C
dc.contributor.authorEverest-Dass, Arun
dc.contributor.authorHansford, Karl A
dc.contributor.authorBolisetti, Raghu
dc.contributor.authorEl-Deeb, Ibrahim M
dc.contributor.authorForde, Brian M
dc.contributor.authorMinh-Duy, Phan
dc.contributor.authorLacey, Jake A
dc.contributor.authorTan, Aimee
dc.contributor.authorJennings, Michael P
dc.contributor.authorvon Itzstein, Mark
dc.contributor.authoret al.
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.publisherAmerican Association for the Advancement of Science (AAAS)
dc.relation.ispartofjournalScience Translational Medicine
dc.subject.fieldofresearchClinical Sciences
dc.subject.fieldofresearchBiological Sciences
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsCell Biology
dc.subject.keywordsMedicine, Research & Experimental
dc.subject.keywordsResearch & Experimental Medicine
dc.titleRepurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationDe Oliveira, DMP; Bohlmann, L; Conroy, T; Jen, FE-C; Everest-Dass, A; Hansford, KA; Bolisetti, R; El-Deeb, IM; Forde, BM; Minh-Duy, P; Lacey, JA; Tan, A; Jennings, MP; von Itzstein, M; et al., Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis, Science Translational Medicine, 2020, 12 (570)
gro.hasfulltextNo Full Text
gro.griffith.authorEverest-Dass, Arun
gro.griffith.authorEl-Deeb, Ibrahim Mustafa
gro.griffith.authorvon Itzstein, Mark
gro.griffith.authorJennings, Michael P.
gro.griffith.authorJen, Freda E.

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