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Title: The role of bilirubin as an anti-microbial agent in neonatal sepsis
Author: Gibson, Sophie
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2015
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Neonatal jaundice is a physiological condition which has potentially deleterious outcomes. Elevated serum bilirubin levels are well-documented antioxidants and have been shown to disrupt cellular membranes of Gram-positive organisms under specific conditions. To determine whether bilirubin had antimicrobial potential against neonatal sepsis organisms, relevant isolates were identified by clinical audit and assessed for sensitivity. 26 clinical isolates including 15 CoNS, 7 GBS, E. coli, E. faecalis, K. oxytoca and A. haemolyticum were characterised biochemically, genetically, and by MALDI Biotype. GBS isolates showed a significant reduction in growth from 100–82.0%(±6.1%), between 0–400μM bilirubin– supplemented CBA (p=0.005). A physiologically relevant liquid model with 100μM bilirubin was developed to test growth reduction. Results showed slight growth reduction in isolates at specific time points, but species specific. Transcriptomic analysis was performed on three GBS isolates to determine effect of bilirubin exposure on gene expression. 17 genes were differentially expressed between 100μM bilirubin and solvent control; 16 up-regulated and one down-regulated with bilirubin. Most significantly, a 5 gene cluster describing multiple components of the phosphotransferase system and two ABC transporter genes were up-regulated, potentially to remove bilirubin from the cell. Proteomic analysis was completed to study protein expression: 12 proteins were identified by LC-MS from 2-DGE and Progenesis SameSpots analysis. Of these, 6 were up- and 6 down-regulated with bilirubin. Up-regulated proteins included two ABC transporter components, phosphoglycerate kinase, S-ribosylhomocysteinase, and two transcription regulators: GroEL/GntR. Down-regulated was iron ABC transporter, NeuB, ornithine carbamoyltransferase and ssDNA binding proteins controlling transcription and translation. This study concluded that bilirubin may play a protective role during the neonatal period; it can be considered an antimicrobial compound which disrupts Grampositive organisms such as GBS, an important agent in early-onset sepsis. The results from this study could be used to develop novel antimicrobial treatments based on identified molecular targets.
Supervisor: Not available Sponsor: Medical Research Council ; NHS Grampian Neonatal Endowment Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Bilirubin ; Septicemia in children ; Newborn infants