H

The mechanism of action of 5-fluorocytosine (5-FC) has been studied in detail and is presented in Figure 6.3. The drug enters the fungal cell by active transport on ATPases that normally transport pyrimidines. Once inside the cell, 5-fluorocytosine is deaminated in a reaction catalyzed by cytosine deaminase to yield 5-fluorouracil (5-FU). 5-Fluorouracil is the active metabolite of the drug. 5-Fluorouracil enters into pathways of both ribonucleotide and deoxyribonucleotide synthesis. The fluororibonu-cleotide triphosphates are incorporated into RNA, causing faulty RNA synthesis. This pathway causes cell death. In the deoxyribonucleotide series, 5-fluorodeoxyuridine monophosphate (F-dUMP) binds to 5,10-methylenete-trahydrofolic acid, interrupting the one-carbon pool substrate that feeds thymidylate synthesis. Hence, DNA synthesis is blocked.

Resistance to 5-FC is very common, and it occurs at several levels. A main one is at the step in which the drug is transported into the fungal cell. The transport system simply becomes impermeable to 5-FC. The cytosine deam-inase step is another point at which resistance occurs, and the UMP pyrophosphorylase reaction is a third point at which fungal cells can become resistant. Regardless of which of these mechanisms operates, fungal resistance develops rapidly and completely when 5-FC is administered. After a few dosing intervals, the drug is essentially useless. One strategy used to decrease resistance and to prolong the effect of 5-FC is to administer it with the polyene antibiotic amphotericin B. The antibiotic creates holes in the fungal cell membrane, bypassing the transport step and allowing 5-FC to enter. Additionally, a lower dose of 5-FC can be used, preventing resistance by other mechanisms for a longer period.

Antifungal Antibiotics27,28

The antifungal antibiotics make up an important group of antifungal agents. All of the antibiotics are marked by their complexity. There are two classes: the polyenes, which contain a large number of agents with only a few being useful, and griseofulvin (one member of the class).

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