Resistance to Systemic Antifungal Agents

Scholer, H. J.; Polak, Annemarie

doi:10.1016/b978-0-12-138120-2.50019-8

Cited by 25 publications

(6 citation statements)

References 130 publications

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“…FA0827 was 15-fold less susceptible to itraconazole than ATCC 6258, which exhibited a susceptible response typical of other published studies on C. krusei (40). The itraconazole-resistant isolate was also crossresistant to ketoconazole but not to amphotericin B, which acts by disrupting membrane function by interacting with ergosterol (25,32). Fluconazole was less active than itraconazole and ketoconazole in inhibiting growth, with both C. krusei isolates exhibiting intrinsic resistance.…”

Section: Resultssupporting

confidence: 58%

Reduced accumulation of drug in Candida krusei accounts for itraconazole resistance

Kanamarlapudi

Denning

Manning

et al. 1996

Antimicrob Agents Chemother

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Due to intrinsic resistance Candida krusei is emerging as a systemic pathogen in AIDS patients undergoing fluconazole therapy, but acquired resistance to itraconazole has not been studied biochemically. We report here studies on the basis for azole resistance and sterol composition in C. krusei. An itraconazole-resistant isolate showed reduced susceptibility to azole drugs in in vitro growth inhibition studies. Accumulation of 14␣-methyl-3,6-diol under azole treatment was associated with growth arrest. In vitro ergosterol biosynthesis and type II binding studies suggested no alteration in the affinity to azole drugs of the target enzyme, the cytochrome P-450 sterol 14␣-demethylase, in the resistant isolate. Resistance was associated with a decreased intracellular content of drug in the resistant isolate.

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Section: Resultssupporting

confidence: 58%

Reduced accumulation of drug in Candida krusei accounts for itraconazole resistance

Kanamarlapudi

Denning

Manning

et al. 1996

Antimicrob Agents Chemother

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“…In contrast, the ergosterol levels in the isolates which were resistant to amphotericin B were comparatively low. This result was expected because amphotericin B acts by interacting with the ergosterol (16). However, we showed in recent studies the existence of amphotericin B resistance in some strains of C. albicans and C. neoformans containing normal levels of ergosterol, and we do not yet know the actual cause for the resistance in these isolates (7,21).…”

Section: Resultsmentioning

confidence: 86%

Fluconazole tolerance in clinical isolates of Cryptococcus neoformans

Kanamarlapudi

Taylor

Manning

et al. 1997

Antimicrob Agents Chemother

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Eleven isolates of Cryptococcus neoformans were investigated to determine the biochemical basis of their tolerance to fluconazole. The MICs of fluconazole for three isolates with low-level resistance were 3- to 6-fold higher than those for sensitive isolates, while the MICs for four isolates with high-level resistance were 100- to 200-fold higher than those for sensitive isolates. The level of ergosterol present in the isolates varied, and those which had relatively low levels of ergosterol were resistant to amphotericin B. Changes in the affinity of the target enzyme (sterol 14alpha-demethylase) and decreases in the cellular content of fluconazole seemed to be responsible for the resistance in isolates with low-level and high-level resistance, respectively.

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“…cycloheximide, benomyl and methotrexate, than S. cerevisiae (Gow et al, 1994;Ben-Yaacov et al, 1994;Prasad, 1991;Fling et al, 1991). In addition, the incidence of C. albicans cells acquiring resistance to azoles and polyenes has increased considerably in recent years, which has posed serious problems towards its successful chemotherapy (Prasad et al, 1996;Vanden Bossche, 1995;Sternberg, 1994;Hitchcock, 1993;Scholer and Polak, 1984). Therefore, the cloning and sequencing of a PDR5 homologue, CDR1 in C. albicans, was an important step to understand the mechanism of drug resistance (Prasad et al, 1995b).…”

Section: Introductionmentioning

confidence: 99%

Deletion of transmembrane domain 12 ofCDR1, a multidrug transporter fromCandida albicans, leads to altered drug specificity: Expression of a yeast multidrug transporter in baculovirus expression system

Krishnamurthy

Chatterjee

Gupta

et al. 1998

Yeast

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Cdr1p, an ATP‐binding cassette transporter from the pathogenic yeast Candida albicans, confers resistance to several unrelated drugs including anti‐Candida drugs (Prasad et al., 1995b). We demonstrate that the deletion of 237 bp (79 aa) from the 3′ end of CDR1 (which encompasses the transmembrane domain (TM) 12 of the putative transporter) did not result in the total loss of its ability to efflux cytotoxic agents. While the expression of ΔCDR1 in yeast resulted in impaired sensitivity to drugs like cycloheximide, anisomycin, sulfomethuron methyl and antifungal nystatin, its ability to confer resistance remained unaltered to drugs such as o‐phenanthroline, 4‐nitroquinoline‐N‐oxide, cerulenin, azoles, oligomycin, erythromycin, and benomyl. Similar to human MDR1p, Cdr1p might also have localized drug binding sites in TM 12, but that might not be the case for all the drugs. The TM 12 deletion also did not lead to any significant impairment in NTPase activities. Both ATPase and UTPase activities of complete Cdr1p and ΔCdr1p were not significantly altered, as was the case with respect to their ability to efflux Rh123 and steroid hormone like [3H]‐β‐estradiol. To further dissect the functionality of Cdr1p, its truncated version was overexpressed in a baculovirus‐insect cell expression system. The synthesis of ΔCdr1p in Sf9 cells was temporally regulated as a function of the baculovirus polyhedrin gene promoter. The Sf9 derived ΔCdr1p was ∼130 kDa, which was lower than the expected size, probably due to the differences in glycosylation. This, however, did not affect the functionality of ΔCdr1p. The deletion of TM 12 did not affect the targeting of the protein and ΔCdr1p was exclusively localized in plasma membrane of Sf9 cells as detected by immunofluorescence. The expression of ΔCdr1p in the baculovirus‐insect expression system generated a high drug‐stimulated plasma membrane‐bound ATPase activity which was not demonstrable when ΔCdr1p was expressed in yeast. © 1998 John Wiley & Sons, Ltd.

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Resistance to Systemic Antifungal Agents

Cited by 25 publications

References 130 publications

Reduced accumulation of drug in Candida krusei accounts for itraconazole resistance

Reduced accumulation of drug in Candida krusei accounts for itraconazole resistance

Fluconazole tolerance in clinical isolates of Cryptococcus neoformans

Deletion of transmembrane domain 12 ofCDR1, a multidrug transporter fromCandida albicans, leads to altered drug specificity: Expression of a yeast multidrug transporter in baculovirus expression system

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