Resistance to amphotericin B associated with defective sterolΔ^8→7isomerase in aCryptococcus neoformansstrain from an AIDS patient

Abstract

Two Cryptococcus neoformans strains isolated from an AIDS patient were investigated, a pretreatment isolate (CN1) and a second isolate (CN3) following failure of fluconazole and amphotericin B treatment. No difference in fluconazole sensitivity, but relative resistance to amphotericin B was observed for CN3. The sterol composition of CN3 indicated a defect in sterol delta 8-->7 isomerase in this strain and depletion of ergosterol, the major sterol of the CN1.

Resistant P45051A1 activity in azole antifungal tolerant Cryptococcus neoformans from AIDS patients

“…Our observation of ergosterol as the predominant sterol of all the strains studied is in accord with a previous study [12,13]. Others have observed lower levels of ergosterol [I 8], but this may have been due to harvesting cells in stationary phase where we have observed a similar effect.…”

“…Sterol analysis did not indicate any overall change in the azole-tolerant clinical isolates as might be conferred by stringent blocks or leaky mutations in enzymes of the ergosterol biosynthetic pathway (Table lb), All strains accumulated approximately 70% ergosterol in accord with our previous analysis of wild-type C. neoformans [13].…”

Amphotericin B resistance of Aspergillus terreus in a murine model of disseminated aspergillosis

“…A similar ergosterol content has been described in a strain of A. fumigatus which is susceptible to amphotericin B in vivo [23,24]. Polyene antifungal resistance has previously been attributed to lesions in the ergosterol biosynthetic pathway in clinical isolates of Candida albicans [22,25,26] and Cryptococcus neoformans [27] and in laboratory mutants of C. albicans [22,28], A. fennelliae [29] and of a protozoan, Leishmania donovani [30]. Nevertheless, amphotericin B resistance has also been reported in C. albicans [31], Cr.…”

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

“…Despite the infrequent prevalence, resistance has still been documented both for clinical isolates and in response to in vitro selection. Amphotericin B-resistant isolates from an AIDS patient were found to have defective ⌬8-7 isomerase activity (274). Furthermore, isolates selected in vitro that were cross-resistant to amphotericin B and fluconazole showed a reduced cellular accumulation of the antifungals, suggesting a possible role for a common multidrug transporter (258).…”