Effects of terconazole and other azole antifungal agents on the sterol and carbohydrate composition of Candida albicans

Pfaller, Michael A.; Riley, John C. M.; Koerner, Theodore A.W.

doi:10.1016/0732-8893(90)90050-6

Cited by 25 publications

(23 citation statements)

References 13 publications

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“…Because of previous reports that azole compounds interfered with the normal synthesis of chitin in the cell wall of Candida albicans (9,18,21) …”

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confidence: 99%

“…Because of previous reports that azole compounds interfered with the normal synthesis of chitin in the cell wall of Candida albicans (9,18,21) and the recent report describing synergy between the nikkomycin complex and three azoles, it seemed appropriate to try various combinations of azoles and purified nikkomycins X (NX) and Z (NZ) RESULTS MIC checkerboard testing. NX and NZ were tested in combination with several azoles by the checkerboard method against C. albicans B311.…”

mentioning

confidence: 99%

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Positive interaction of nikkomycins and azoles against Candida albicans in vitro and in vivo

Hector

Schaller

1992

Antimicrob Agents Chemother

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Nikkomycins X and Z (NZ), competitive inhibitors of fungal chitin synthetase, were combined with azoles in a series of in vitro checkerboard assays to test for synergism against Candida spp. All combinations of nikkomycins and azoles tested resulted in marked synergistic activity against an isolate of Candida albicans, with fractional inhibitory concentration indices ranging from 0.016 to 0.28. No synergistic effect was demonstrable with isolates of C. tropicalis, C. parapsilosis, or C. krusei, though results for the latter two were suggestive of an additive effect. In survival models of mice infected intravenously with C. albicans, NZ administered singly in doses ranging from 5 to 50 mg/kg of body weight twice a day was able to delay the onset of mortality but showed no dose-response effect. The combination of NZ and the azole R 3783 administered orally in a ratio of 8:1 to 40:1 or greater (wt/wt) enhanced survival better than did the drugs given individually, but this effect was less evident for combinations involving fluconazole. In short-term organ load assays with outbred mice infected intravenously with C. albicans, high ratios of NZ to R 3783 reduced the CFU per gram in kidneys more significantly than did the drugs individually. Statistically significant reductions were not seen for short-term fungal burden assays using combinations of NZ and fluconazole in outbred mice or in inbred mice more susceptible to candidiasis. In a model of rat vaginal candidiasis, the combination of NZ and R 3783 administered either orally or vaginally was more effective than the drugs used singly. Thus, under certain conditions, combination therapy with nikkomycin and select azoles may offer promise for an increased therapeutic effect in candidiasis.With the increase in the number of immunocompromised patients in the last decade, there has been a concomitant increase in the numbers of life-threatening mycoses (17,20).Unfortunately, antifungal drugs released for clinical use over the last decade have not offered substantive improvements in efficacy over amphotericin B. Recently, several new compounds active against the cell walls of fungi have been evaluated. These compounds include derivatives of echinocandin B, which inhibit beta-glucan synthesis (6,22), and the nikkomycins, which inhibit chitin synthesis (4). While these drugs show promise, their spectrum of activity appears to be limited in comparison to those of the azoles and amphotericin B (6, 12). Previous data obtained with nikkomycin used as therapy in a mouse model of candidiasis showed only modest efficacy (1).One approach to increasing the therapeutic index of anti-infective drugs is to test them in combinations for synergistic interactions. While there have been a number of reports concerning positive interactions of antifungal drugs or antifungal and antibacterial drugs, few combinations have shown substantial improvements over the effects of the single drugs; many have shown antagonism (2,3,5,13,16,19,23).Because of previous reports that azole compounds interfer...

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“…Because of previous reports that azole compounds interfered with the normal synthesis of chitin in the cell wall of Candida albicans (9,18,21) …”

mentioning

confidence: 99%

mentioning

confidence: 99%

Positive interaction of nikkomycins and azoles against Candida albicans in vitro and in vivo

Hector

Schaller

1992

Antimicrob Agents Chemother

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“…This phenomenon is probably a result of the previously described secondary effects of azoles on chitin synthesis (107,188,255) being compounded by the specific inhibition of this polymer by nikkomycin. The usefulness of this approach has yet to be determined because the effect is limited to certain ratios of the two compounds, making dosing problematic.…”

Section: Combinations Of Cell Wall-active Substancesmentioning

confidence: 88%

Compounds active against cell walls of medically important fungi

Hector

1993

Clin Microbiol Rev

216

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A number of substances that directly or indirectly affect the cell walls of fungi have been identified. Those that actively interfere with the synthesis or degradation of polysaccharide components share the property of being produced by soil microbes as secondary metabolites. Compounds specifically interfering with chitin or beta-glucan synthesis have proven effective in studies of preclinical models of mycoses, though they appear to have a restricted spectrum of coverage. Semisynthetic derivatives of some of the natural products have offered improvements in activity, toxicology, or pharmacokinetic behavior. Compounds which act on the cell wall indirectly or by a secondary mechanism of action, such as the azoles, act against diverse fungi but are usually fungistatic in nature. Overall, these compounds are attractive candidates for further development.

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“…As expected, the results shown in Table 4 indicate that Δcsn5 cells are indeed more sensitive to ketoconazole and more resistant to nystatin compared with the wild-type, again confirming an alteration in ergosterol biosynthesis. The ergosterol reduction observed in the Δcsn5 strain is within the range (12-51%) observed in yeast cells treated with different azole derivatives at sub-inhibitory concentrations (0.01-1 lMÁL À1 ) [32,33]. At higher azole concen-…”

Section: The δCsn5 Mutant Has Reduced Ergosterol Contentmentioning

confidence: 91%

The COP9 signalosome is involved in the regulation of lipid metabolism and of transition metals uptake in Saccharomyces cerevisiae

et al. 2013

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The COP9 signalosome (CSN) is a highly conserved eukaryotic protein complex which regulates the cullin RING family of ubiquitin ligases and carries out a deneddylase activity that resides in subunit 5 (CSN5). Whereas CSN activity is essential for the development of higher eukaryotes, several unicellular fungi including the budding yeast Saccharomyces cerevisiae can survive without a functional CSN. Nevertheless, the budding yeast CSN is biochemically active and deletion mutants of each of its subunits exhibit deficiency in cullins deneddylation, although the biological context of this activity is still unknown in this organism. To further characterize CSN function in budding yeast, we present here a transcriptomic and proteomic analysis of a S. cerevisiae strain deleted in the CSN5/RRI1 gene (hereafter referred to as CSN5), coding for the only canonical subunit of the complex. We show that Csn5 is involved in modulation of the genes controlling amino acid and lipid metabolism and especially ergosterol biosynthesis. These alterations in gene expression correlate with the lower ergosterol levels and increased intracellular zinc content which we observed in csn5 null mutant cells. We show that some of these regulatory effects of Csn5, in particular the control of isoprenoid biosynthesis, are conserved through evolution, since similar transcriptomic and/or proteomic effects of csn5 mutation were previously observed in other eukaryotic organisms such as Aspergillus nidulans, Arabidopsis thaliana and Drosophila melanogaster. Our results suggest that the diverged budding yeast CSN is more conserved than was previously thought.

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Effects of terconazole and other azole antifungal agents on the sterol and carbohydrate composition of Candida albicans

Cited by 25 publications

References 13 publications

Positive interaction of nikkomycins and azoles against Candida albicans in vitro and in vivo

Positive interaction of nikkomycins and azoles against Candida albicans in vitro and in vivo

Compounds active against cell walls of medically important fungi

The COP9 signalosome is involved in the regulation of lipid metabolism and of transition metals uptake in Saccharomyces cerevisiae

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