5-fluorocytosine antagonizes the action of sterol biosynthesis inhibitors in Candida glabrata

The concentration-dependent antagonistic interaction between 5-fluorocytosi ne and a sterol biosynthesis inhibitor (SBI) was studied using intact cells and cell-free extracts of Candida glabrata. 5-fluorocytosine promoted inco rporation of radioactivity into 4-desmethylsterols (P < 0.01), and enhanced the relative and absolute increases of ergosterol (P < 0.05) in C. glabrat a incubated aerobically with an SBI (miconazole or amorolfine). Further aer obic incubation of C. glabrata with combinations of a nucleic acid or prote in synthesis inhibitor (rifampicin or chlortetracycline) and an SBI (micona zole) promoted a similar increase in ergosterol biosynthesis. In contrast, 5-fluorocytosine reduced the incorporation of radioactivity into 4,4-dimeth ylsterols (P < 0.01), but had no obvious effect on the absolute ergosterol level in C. glabrata incubated statically with miconazole. In cell-free ext racts of cultures previously incubated with 5-fluorocytosine, ergosterol sy nthesis was less sensitive to the action of miconazole. Antagonism between 5-fluorocytosine and the SBI is thus mediated by a reversal of inhibition o f intracellular ergosterol synthesis. The possible mechanisms underlying an tagonism between 5-fluorocytosine and SBIs that inhibit different sites of the sterol biosynthesis pathway, as well as its clinical relevance to combi nation therapy, are discussed.