Antimicrobial resistance is a critical issue in the continued treatment of infectious diseases. AraC-type transcriptional regulators, such as SoxS, RamA, MarA, and Rob, have been shown to be associated with multidrug resistance in clinically relevant Gram-negative bacteria, in addition to playing diverse roles including metabolism and virulence. As such, the increased expression of these proteins is likely to cause pleiotropic phenotypes that extend beyond antimicrobial resistance. This thesis characterizes a novel homologue of these proteins, RarA, which is encoded in some members of the Enterobacteriaceae. In characterising this regulator, our data shows that the overexpression of, rarA results in a low level multidrug resistance phenotype, which is largely conferred through the upregulation of AcrAB and the recently-characterised OqxAB efflux pumps. Transcriptome analyses in K pneumoniae support the wider role of RarA in gene regulation, as RarA regulates genes involved in cell envelope biogenesis and posttranslational modification, previously uncharacterized transport proteins, energy production/conversion and amino acid transport/metabolism. In support of the transcriptome analyses, Biolog phenotype microarray profiling shows that RarA overexpression confers enhanced growth in the presence of several antibiotic classes, in addition to resistance to previously unreported disinfectant agents and antifungal compounds (c1ioquinol, B-hydroxyquinoline). The central role of RarA in resistance to myriad compounds is also relevant in the development of tigecycline resistance in K pneumoniae and ,Enterobacter spp. Intrinsic mechanisms offer microbial survival strategies in the face of continued antibiotic pressure and such mechanisms are not well characterised in K. pneumoniae. As such this study has characterised and described the role of a transcriptional regulator, RarA, which plays a role in the intrinsic K Pneumoniae resistome.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:602949 |
| Date | January 2013 |
| Creators | Veleba, Mark |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
Page generated in 0.0018 seconds