Journal of Antimicrobial Chemotherapy (1999) 43, 767-775
© 1999 The British Society for Antimicrobial Chemotherapy
5-Fluorocytosine antagonizes the action of sterol biosynthesis inhibitors in Candida glabrata
Department of Biochemistry, University of Cambridge, Cambridge, UK
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.
* Correspondence address. Department of Microbilogy, Univesity of Hong Kong, University Pathology Building, Queen Mary Hospital Compound, Pokfalum Road, Hong Kong. Tel: +852-2855-4891; Fax: +852-2855-1241; E-mail: hongsiau{at}hkusua.hku.hk
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