A 5-fluorocytosine-sensitive isolate of Candida albicans was examined for the presence of thymidylate synthetase activity and 5-fluoro-2′-deoxyuridylic acid in the presence and absence of a growth-inhibiting concentration of 5-fluorocytosine. Initial studies demonstrated thymidylate synthetase activity in a crude homogenate prepared from this isolate. This activity could be inhibited by preincubating the homogenate with 5-fluoro-2′-deoxyuridylic acid. Evidence is presented suggesting that the inhibition of this enzyme is irreversible. Later studies measured thymidylate synthetase activity and 5-fluoro-2′-deoxyuridylic acid levels in homogenates prepared from harvested C. albicans after varying intervals of exposure to 100 μg/ml of 5-fluorocytosine. Thymidylate synthetase activity was observed to be 20 per cent of control after 1 hr of exposure to 5-FC, remaining decreased through the remainder of the 24 hr. 5-fluoro-2′-deoxyuridylate was measurable at all of the time points examined in the fungal cells exposed to 5-fluorocytosine in levels from 2 to 40 pmoles/μg of DNA while no evidence was found for this compound in the controls. In light of these findings, it is suggested that inhibition of thymidylate synthetase activity by endogenously synthesized 5-fluoro-2′-deoxyuridylic acid is a possible mechanism by which 5-fluorocytosine exerts its antifungal effect.
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