Thesis

Comparative efficacy of azole compounds targeting sterol 14-demethylase against multiple isolates of Acanthamoeba castellanii and polyphaga

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Awarding institution
  • University of Strathclyde
Date of award
  • 2014
Thesis identifier
  • T13813
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Abstract
  • The species of the genus Acanthamoeba are normally free-living protozoan parasites, found ubiquitously in the environment. However, they are also have the ability to parasitise humans where they cause a variety of diseases depending upon the anatomical site of infection and the immune status of the host. The most common infection caused by Acanthamoeba spp. in immunocompetent humans is Acanthamoeba keratitis a severe infection of the eye that has increased in prevalence mainly due to the increase in the use of contact lenses. Current methods of treatment for Acanthamoeba keratitis are sporadic in effectiveness and no standard treatment regime currently exists. Consequently better drugs and treatments are required. Ergosterol is a sterol found both in fungi and certain strains of amoeba including Acanthamoeba spp. but does not occur in animals, it is a vital part of the membrane serving the same function as cholesterol in mammals this renders its synthesis an attractive drug target in Acanthamoeba. Azoles are an antifungal medication that target the cytochrome P450 enzyme sterol 14-demethylase, this enzyme is essential in the ergosterol pathway and its inhibition results in the loss of membrane stability and cell death. In this study five azoles; Econazole, Miconazole, Sulconazole, Tioconazole and Voriconazole where tested for effectiveness against several isolates of two species of Acanthamoeba. Acanthamoeba castellanii and Acanthamoeba polyphaga using a modified colorimetric assay. Sequence analysis was also carried out in order to prove the existence of the putative target enzyme of the azoles. The results indicate that azoles have an inhibitory effect on Acanthamoeba spp. growth although the effectiveness of each drug differed significantly between individual isolates. Tioconazole and Voriconazole had the greatest overall inhibition for all species and isolates tested. The results from this study show that azoles are a potential treatment path for Acanthamoeba keratitis. Sequence analysis shows that sterol 14-demethylase and its immediate enzyme pathway is highly conserved between Acanthamoeba spp.
Resource Type
DOI
Date Created
  • 2014
Former identifier
  • 1038803

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