Mechanism and resistance of flucytosine

5-FC enters fungal cells via a cytosinespecific permease, which is an enzyme not found in mammalian cells. 5-FC is then converted by a series of steps to 5-fluorodeoxyuridine 5’ monophosphate. This false nucleotide inhibits thymidylate synthase, thereby depriving the organism of thymidylic acid, an essential DNA component The unnatural mononucleotide is further metabolized to a trinucleotide (5-fl uorodeoxyuridine 5’-triphosphate) and is incorporated into fungal RNA, where it disrupts nucleic acid and protein synthesis. [Note: Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell.Thus, 5-FC and amphotericin B are synergistic  Flucytosine is accumulated in fungal cells by the action of a membrane permease and converted by cytosine deaminase to 5-FU, an inhibitor of thymidylate synthase Selective toxicity occurs because mammalian cells have low levels of permease and deaminase. Resistance can occur rapidly if flucytosine is used alone and involves decreased activity of the fungal permeases or deaminases. When 5-FC is given with amphotericin B, or triazoles such as itraconazole, emergence of resistance is decreased and synergistic antifungal effects may occur