Fatty acid synthase 1 in Candida albicans virulence and the in vitro effects of fluconazole, tetracycline in combinatorial therapy

Candida albicans, the causative agent of superficial and invasive mycoses, is a significant fungal pathogen associated with high mortality rates and considerable health-related costs. The most effective class of antifungals used for the treatment of candidiasis includes polyenes, echinocandins and azoles. However with the emergence of resistant strains, new antifungals are warranted for the effective treatment of candidiasis. Genes involved in biosynthetic enzymatic pathways that regulate metabolic processes are important for the survival of pathogenic fungi and can thus be exploited for the development of better antifungals. Fatty acid synthase 1, which is involved in the de novo biosynthesis of fatty acids in C. albicans and disruption of the FAS1 gene affects the survival and virulence of C.albicans in the host and could thus be an ideal drug target. Disruption of the FAS1 gene resulted in significant modifications in the membrane fatty acid composition, thus resulting in altered membrane permeability to membrane stress-inducing agents, resulting in hypersensitivity of the mutant to osmotic stress. The potentiation of the antifungal effect of fluconazole by its combination with tetracycline was also examined in this thesis. These drugs act in synergy and are fungicidal against C.albicans in vitro and the mechanism for this synergy was explored. The drug combination was demonstrated to exert its fungicidal activity against C.albicans by affecting its mitochondrial function by disrupting its membrane potential and activity of mitochondrial dehydrogenases.