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dc.contributor.authorAbdul Rahim, N
dc.contributor.authorZhu, Y
dc.contributor.authorCheah, SE
dc.contributor.authorJohnson, MD
dc.contributor.authorYu, HH
dc.contributor.authorSidjabat, HE
dc.contributor.authorButler, MS
dc.contributor.authorCooper, MA
dc.contributor.authorFu, J
dc.contributor.authorPaterson, DL
dc.contributor.authorNation, RL
dc.contributor.authorBoyce, JD
dc.contributor.authorCreek, DJ
dc.contributor.authorBergen, PJ
dc.contributor.authorVelkov, T
dc.contributor.authorLi, J
dc.date.accessioned2021-05-25T01:34:02Z
dc.date.available2021-05-25T01:34:02Z
dc.date.issued2021
dc.identifier.issn2373-8227
dc.identifier.doi10.1021/acsinfecdis.0c00661
dc.identifier.urihttp://hdl.handle.net/10072/404636
dc.description.abstractCarbapenem-resistant Klebsiella pneumoniae has been classified as an Urgent Threat by the Centers for Disease Control and Prevention (CDC). The combination of two "old"antibiotics, polymyxin and chloramphenicol, displays synergistic killing against New Delhi metallo-β-lactamase (NDM)-producing K. pneumoniae. However, the mechanism(s) underpinning their synergistic killing are not well studied. We employed an in vitro pharmacokinetic/pharmacodynamic model to mimic the pharmacokinetics of the antibiotics in patients and examined bacterial killing against NDM-producing K. pneumoniae using a metabolomic approach. Metabolomic analysis was integrated with an isolate-specific genome-scale metabolic network (GSMN). Our results show that metabolic responses to polymyxin B and/or chloramphenicol against NDM-producing K. pneumoniae involved the inhibition of cell envelope biogenesis, metabolism of arginine and nucleotides, glycolysis, and pentose phosphate pathways. Our metabolomic and GSMN modeling results highlight the novel mechanisms of a synergistic antibiotic combination at the network level and may have a significant potential in developing precision antimicrobial chemotherapy in patients.
dc.description.peerreviewedYes
dc.languageeng
dc.publisherAmerican Chemical Society (ACS)
dc.relation.ispartofjournalACS Infectious Diseases
dc.subject.fieldofresearchMedical microbiology
dc.subject.fieldofresearchcode3207
dc.subject.keywordsKlebsiella pneumoniae
dc.subject.keywordsNew Delhi metallo-β-lactamase
dc.subject.keywordscombination therapy
dc.subject.keywordspolymyxin
dc.subject.keywordssystems pharmacology
dc.titleSynergy of the Polymyxin-Chloramphenicol Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae Is Predominately Driven by Chloramphenicol
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationAbdul Rahim, N; Zhu, Y; Cheah, SE; Johnson, MD; Yu, HH; Sidjabat, HE; Butler, MS; Cooper, MA; Fu, J; Paterson, DL; Nation, RL; Boyce, JD; Creek, DJ; Bergen, PJ; Velkov, T; Li, J, Synergy of the Polymyxin-Chloramphenicol Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae Is Predominately Driven by Chloramphenicol, ACS Infectious Diseases, 2021
dc.date.updated2021-05-23T23:33:00Z
gro.description.notepublicThis publication has been entered in Griffith Research Online as an advanced online version.
gro.hasfulltextNo Full Text
gro.griffith.authorSidjabat, Hanna E.


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