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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.date.accessioned2021-01-08T04:18:29Z
dc.date.available2021-01-08T04:18:29Z
dc.date.issued2020
dc.identifier.issn1946-6234
dc.identifier.doi10.1126/scitranslmed.abb3791
dc.identifier.urihttp://hdl.handle.net/10072/400806
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.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Association for the Advancement of Science (AAAS)
dc.relation.ispartofissue570
dc.relation.ispartofjournalScience Translational Medicine
dc.relation.ispartofvolume12
dc.subject.fieldofresearchClinical Sciences
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchBiological Sciences
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchcode1103
dc.subject.fieldofresearchcode0605
dc.subject.fieldofresearchcode06
dc.subject.fieldofresearchcode11
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)
dcterms.dateAccepted2020-10-30
dc.date.updated2021-01-08T04:14:07Z
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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