5-Fluorocytosine antagonizes the action of sterol biosynthesis inhibitors in Candida glabrata.
The concentration-dependent antagonistic interaction between 5-fluorocytosine and a sterol biosynthesis inhibitor (SBI) was studied using intact cells and cell-free extracts of Candida glabrata. 5-Fluorocytosine promoted incorporation of radioactivity into 4-desmethylsterols (P < 0.01), and enhanced the relative and absolute increases of ergosterol (P < 0.05) in C. glabrata incubated aerobically with an SBI (miconazole or amorolfine). Further aerobic incubation of C. glabrata with combinations of a nucleic acid or protein synthesis inhibitor (rifampicin or chlortetracycline) and an SBI (miconazole) promoted a similar increase in ergosterol biosynthesis. In contrast, 5-fluorocytosine reduced the incorporation of radioactivity into 4,4-dimethylsterols (P < 0.01), but had no obvious effect on the absolute ergosterol level in C. glabrata incubated statically with miconazole. In cell-free extracts of cultures previously incubated with 5-fluorocytosine, ergosterol synthesis was less sensitive to the action of miconazole. Antagonism between 5-fluorocytosine and the SBI is thus mediated by a reversal of inhibition of intracellular ergosterol synthesis. The possible mechanisms underlying antagonism between 5-fluorocytosine and SBIs that inhibit different sites of the sterol biosynthesis pathway, as well as its clinical relevance to combination therapy, are discussed.
Department of Biochemistry, University of Cambridge, UK. hongsiau@hkusua.hku.hk
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D000935:Antifungal Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002175:Candida / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002474:Cell-Free System / Q000378:metabolism; D004336:Drug Antagonism; D004875:Ergosterol / Q000096:biosynthesis*; D005437:Flucytosine / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008825:Miconazole / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009025:Morpholines / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000935:Antifungal Agents; D009025:Morpholines; D008825:Miconazole; C038974:amorolfine; D005437:Flucytosine; D006903:Hydroxymethylglutaryl CoA Reductases; D004875:Ergosterol