Date of Award

12-1-2004

Degree Type

Thesis

University or Center

Clark Atlanta University(CAU)

Degree Name

M.S.

Biological Sciences

First Advisor

David Logan

Second Advisor

Paul McGeady

Third Advisor

Juarine Stewart

Abstract

Mucor racemosus is a saprophytic, dimorphic fungus belonging to the order Mucorales. The fungus grows as branching, filamentous mycelia in an aerobic environment, but under anaerobic conditions, in the presence of a fermentable hexose, the fungus exhibits its budding yeast form. Though Mucor species are usually not pathogens, several species, including M. racemosus, are among the various Zygomycetes identified as causing a type of opportunistic fungal disease in humans called mucormycosis.

The objective of this study was to obtain information regarding the effects of protein prenylation inhibitors on morphogenesis in M. racemosus. The prenylation inhibitors used were carvone (250 uJvl), perillaldehyde (250 \M) and farnesyl-protein transferase inhibitor type m (FPT III) (200 ^iM). We hypothesized that exposure of M. racemosus to the protein prenylation inhibitors carvone, perillaldehyde, and FPT III would result in inhibition of spore-to-hyphal and yeast-to-hyphal morphogenesis.

In the spore-to-hyphal studies results showed the inhibitors delayed morphogenesis by 1 hour in Mucor cells. There was a significant difference in sporeto- hyphal morphogenesis between control cells and cells treated with the inhibitors in the earlier hours of incubation (5-7 h). However, as a possible result of cell metabolism, by the 9th h all cells developed 100 % hyphae.

Following redosing with the inhibitors at the 5th h (start of germ tube emergence) of incubation, germ tube emergence was delayed by an additional hour and hyphal formation was significantly suppressed in the later hours of incubation (8-10 h). These results suggested the cells were metabolizing the drugs.

During the yeast-to-hyphal studies, as the percentage of cells with buds decreased, percent germ tube and hyphal formation increased. These results showed successful yeast-to-hyphal morphogenesis. Following 24 hours of growth, cells treated with the inhibitors still contained budding yeast cells compared to the control, which had no presence of budding yeast cells and 100 % hyphal development. Results showed the inhibitors significantly delayed yeast-to-hyphal morphogenesis.

Spore-to-hyphal and yeast-to-hyphal morphogenesis was delayed by the prenylation inhibitors as shown by lower percentages of germ tubes, weights, and protein concentration levels in cells treated with the inhibitors compared to the control samples. The experiments conducted with these protein prenylation inhibitors provided evidence that with repeated doses, conversion ofM. racemosus to its pathogenic hyphal form can effectively be delayed and possibly inhibited. Further studies with these drugs and other compounds should provide more information on the potential of prenylation inhibitors to be used in the treatment of mucormycosis and other pathogenic fungal diseases.

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