Novel treatments for, and physiology of, Candida albicans
The potential application of weak acids for prevention of germ tube formation, a pathogenic process in Candida albicans, was examined. Previous departmental work revealed a rapid cytoplasmic alkalinization prior to germ tube formation in normal but not hyphal-minus strains, suggesting involvement of cytoplasmic alkalinization in dimorphism. Evidence that benzoate and sorbate can prevent germ tube formation and inhibit growth is given. This is probably due to their ability to shuttle protons across the plasma membrane perturbing intracellular pH control via the ATPase. Benzoate and sorbate could therefore provide an excellent and novel treatment for thrush infections based on a central cellular requirement, that of pH control. In addition they are relatively harmless, cheap and plentiful. The extent to which the azoles affect cellular functions other than ergosterol biosynthesis is unknown. Three separate effects have been identified here which suggest three target sites. High concentrations of azole result in cell death, intermediate concentrations in inhibition of germ tube extension and low concentrations in inhibition of dimorphism. It is already known that fluconazole inhibits cytoplasmic alkalinization and germ tube formation and that azoles inhibit the ATPase. This suggests a relationship between azoles and dimorphism which may be linked through their effect on intracellular pH by direct or indirect interference with ATPase activity. The occurrence of synergism between weak acids and the azoles has been confirmed. This provides the basis for work towards a novel treatment for thrush infections since synergistic relationships enhance effect and delay development of resistance. Growth of Candida albicans hyphae on a solid surface results in the production of a so far unreported coiled morphology. Investigations show that this is probably the result of tip rotation during apical extension which is revealed as a result of adherence to a solid surface. In addition evidence has been obtained of the frequency with which hyphae enter the random pores of Nucleopore membranes. This suggests the possibility (and emphasizes the need for investigation) of contact mediated responses in Candida albicans. Both hyphal coiling and the possibility of contact mediated responses are landmarks in pathogenicity studies of Candida albicans.