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|Title: ||The dissemination and expression of the carbapenem- hydrolyzing enzyme blaOXA-23|
|Authors: ||Valenzuela, Jubelle Kristine|
|Issue Date: ||30-Aug-2010|
|Publisher: ||University of Sydney|
School of Medicine
|Abstract: ||Carbapenems are currently the ‘last line’ antimicrobial therapeutics prescribed against persistent bacterial infections. Resistance to this class of drug is therefore, clinically significant. Reports of carbapenem resistance, especially in Acinetobacter baumannii and Pseudomonas aeruginosa, are increasing worldwide. Studies have shown that carbapenem resistance can be attributed to altered drug targets; defects in outer membrane proteins, over-expressed efflux mechanisms and or the activity of a carbapenem-hydrolysing enzyme.
A retrospective study of the emergence of carbapenem-resistant A. baumannii in Australian hospitals has shown that the activity of a carbapenemase gene, blaOXA-23 was the cause of resistance. The epidemiological study revealed that six related strains of A. baumannii conferred the carbapenem-resistant phenotype. In this epidemic, blaOXA-23 was disseminated by a composite transposon, a mobile genetic element similar to Tn2006. The transposition of Tn2006 is controlled by a transposase encoded by the IS element ISAba1.
In addition to transposition, ISAba1 has also been shown to provide a strong promoter for the expression of blaOXA-23. ISAba1 promoter studies demonstrated that the presence of ISAba1-blaOXA-23 in E. coli does not affect susceptibility to carbapenems. This suggests that other factors such as bacterial host’s outer membrane permeability may contribute to the carbapenem-resistant phenotype. The effect of the host cell’s outer membrane permeability was investigated in P. aeruginosa isolates with outer membrane protein defects. These studies show that P. aeruginosa isolates with specific mutations in outer membrane protein OprD were carbapenem-resistant. The transformation of carbapenemase genes into OprD-defective P. aeruginosa isolates decreased susceptibility to carbapenems. Collectively, carbapenem resistance has been shown to be a complex interaction between host cell permeability, enzyme hydrolysing activity and gene expression.|
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|Rights and Permissions: ||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work: ||PhD Doctorate|
|Type of Publication: ||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
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|Jubelle Kristine Valenzuela - Final Thesis.pdf||Thesis||2.31 MB||Adobe PDF|
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