The main aim of this project was to determine the potential of increased chitin content as a mechanism of resistance to caspofungin in different fungal pathogens. <i>C. albicans</i> wild-type cells were pre-grown with a combination of CaCl<sub>2</sub> and CFW prior to caspofungin treatment. This result sin a three-fold increase in cell wall chitin. Wild-type cells, which had elevated chitin content, were less susceptible to caspofungin. Priming cells to activated chitin synthesis was also able to compensate for the loss of the normally essential <i>CaCHS1</i>, through formation of three novel forms of salvage septa. In the absence of both <i>Ca</i>Chs1 and <i>Ca</i>Chs3, which are typically involved in septum formation, the class I chitin synthases, <i>Ca</i>Chs2 and <i>Ca</i>Chs8, could be stimulated to synthesise a proximally offset salvage septum. When <i>Ca</i>Chs3 was the only remaining chitin synthase, treatment with CaCl<sub>2</sub> and CFW, led to the formation of thick chitin-rich salvage septa. <i>Ca</i>Chs2<i> </i>and <i>Ca</i>Chs3 could be stimulated by treatment with CaCl<sub>2</sub> and CFW to synthesise a thin salvage septum similar to the septum of wild-type cells. All three salvage septa were capable of restoring viability and cell division in <i>C. albicans.</i> The compensatory increase in chitin content in response to caspofungin treatment was not specific to <i>C. albicans</i> because clinical isolates of <i>C. tropicalis, C. parapsilosis </i>and <i>C. guilliermondii</i> and the filamentous fungus, <i>A. fumigatus</i>, also demonstrated an increase in chitin content after treatment with caspofungin. Isolates of <i>C. glabrata</i> and <i>C. krusei</i> showed no change in chitin content when exposed to caspofungin. The results of this thesis highlight the potential for using chitin synthase inhibitors in combination therapy with the echinocandins.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:522067 |
| Date | January 2010 |
| Creators | Walker, Louise |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=136783 |
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