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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.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.en_US
dc.publisherAmerican Chemical Society (ACS)en_US
dc.relation.ispartofjournalACS Infectious Diseasesen_US
dc.subject.fieldofresearchMedical Microbiologyen_US
dc.subject.keywordsKlebsiella pneumoniaeen_US
dc.subject.keywordsNew Delhi metallo-β-lactamaseen_US
dc.subject.keywordscombination therapyen_US
dc.subject.keywordssystems pharmacologyen_US
dc.titleSynergy of the Polymyxin-Chloramphenicol Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae Is Predominately Driven by Chloramphenicolen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
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, 2021en_US
gro.description.notepublicThis publication has been entered in Griffith Research Online as an advanced online version.en_US
gro.hasfulltextNo Full Text
gro.griffith.authorSidjabat, Hanna E.

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