Mode of Action of the Polyene Antibiotic Candicidin: Binding Factors in the Wall of
            <i>Candida albicans</i>

Hammond, Stephen M.; Kliger, B. N.

doi:10.1128/aac.9.4.561

Cited by 23 publications

(9 citation statements)

References 21 publications

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“…3). On the basis of the absorbance of the peaks, we could be certain that L and C had <10% of the ergosterol content of C. albicans B311, which contained a standard level (8).…”

Section: Resultsmentioning

confidence: 99%

Role of cell defense against oxidative damage in the resistance of Candida albicans to the killing effect of amphotericin B

Sokol-Anderson

Sligh

Elberg

et al. 1988

Antimicrob Agents Chemother

102

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A laboratory-derived mutant of Candida albicans B311 (L) and a clinical isolate (C) of C. albicans, both lacking membrane ergosterol, were less susceptible to amphotericin B (AmB)-induced cell membrane permeability to K+ and lethality than was the wild-type laboratory strain (B311) which contained ergosterol. The resistance of L and C to AmB-induced killing was much greater than the level of resistance to AmB-induced cell membrane permeability. L and C were also less susceptible to killing by H202 than was B311, and when treated with menadione, they each produced less H202 than did B311. In addition, their levels of catalase activity were 3.8-fold (L) and 2-fold (C) higher than that of B311. The ergosterol deficiency in L and C probably impaired AmB binding to the cells, thereby lowering AmB effectiveness as measured by both cell membrane permeability and killing. Resistance of strains L and C to oxidation-dependent damage likely contributed to a diminished response to AmB-induced lethality.

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“…3). On the basis of the absorbance of the peaks, we could be certain that L and C had <10% of the ergosterol content of C. albicans B311, which contained a standard level (8).…”

Section: Resultsmentioning

confidence: 99%

Role of cell defense against oxidative damage in the resistance of Candida albicans to the killing effect of amphotericin B

Sokol-Anderson

Sligh

Elberg

et al. 1988

Antimicrob Agents Chemother

102

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“…Although candicidins are highly active antifungals, their medical use is restricted to severe cases (28). Like other polyketide polyenes, candicidins interact with sterols in the fungal cell membranes, causing K ϩ -leakage and inducing cell death (29). The relatively rare development of resistance to polyketide polyenes among pathogenic fungi (28) might explain why leaf-cutting ants benefit from the presence of candicidinproducing microorganisms and do not face the risk that Escovopsis will adapt quickly.…”

Section: Discussionmentioning

confidence: 99%

Candicidin-producing Streptomyces support leaf-cutting ants to protect their fungus garden against the pathogenic fungus Escovopsis

Haeder

Wirth

Herz

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

265

216

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Leaf-cutting ants such as Acromyrmex octospinosus live in obligate symbiosis with fungi of the genus Leucoagaricus, which they grow with harvested leaf material. The symbiotic fungi, in turn, serve as a major food source for the ants. This mutualistic relation is disturbed by the specialized pathogenic fungus Escovopsis sp., which can overcome Leucoagaricus sp. and thus destroy the ant colony. Microbial symbionts of leaf-cutting ants have been suggested to protect the fungus garden against Escovopsis by producing antifungal compounds [Currie CR, Scott JA, Summerbell RC, Malloch D (1999) Fungus-growing ants use antibiotic-producing bacteria to control garden parasites. Nature 398:701-704.]. To date, however, the chemical nature of these compounds has remained elusive. We characterized 19 leaf-cutting ant-associated microorganisms (5 Pseudonocardia, 1 Dermacoccus, and 13 Streptomyces) from 3 Acromyrmex species, A. octospinosus, A. echinatior, and A. volcanus, using 16S-rDNA analysis. Because the strain Streptomyces sp. Ao10 proved highly active against the pathogen Escovopsis, we identified the molecular basis of its antifungal activity. Using bioassay-guided fractionation, high-resolution electrospray mass spectrometry (HR-ESI-MS), and UV spectroscopy, and comparing the results with an authentic standard, we were able identify candicidin macrolides. Candicidin macrolides are highly active against Escovopsis but do not significantly affect the growth of the symbiotic fungus. At least one of the microbial isolates from each of the 3 leaf-cutting ant species analyzed produced candicidin macrolides. This suggests that candicidins play an important role in protecting the fungus gardens of leaf-cutting ants against pathogenic fungi.Acromyrmex ͉ antifungal agent ͉ symbionts ͉ Attini ͉ polyketides

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“…We assume that the receptors for the nontoxic binding are fatty acids located in the cell wall of C. albicans (5). Others have shown that polyenes can bind to fatty acids (2,5), but it is worth noting that whereas both sterols (3) and fatty acid (6) (8,12). In an experiment similar to the one described for AmB, low concentrations of miconazole induced an increase in colony-forming units comparable to that caused by the polyene antibiotics (data not shown).…”

mentioning

confidence: 99%

Increase in colony-forming units of Candida albicans after treatment with polyene antibiotics

Brajtburg¹,

Elberg²,

Medoff³

et al. 1981

Antimicrob Agents Chemother

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Polyene antibiotics, at concentrations which do not cause detectable toxic effect, induce an increase in the number of colony-forming units of yeast cells of Candida albicans. This effect, which we attribute to an increase in plating efficiency, is probably caused by binding of the polyenes to fatty acids in the cell wall of fungi.The toxic effects of polyene antibiotics on fungi are generally attributed to the binding of the polyenes to cell membrane sterols (4, 11). However, binding can also occur without toxicity (7). In this study we show that under conditions in which polyenes are not toxic to yeast cells of Candida albicans (low concentration of antibiotic, or low incubation temperature), they can increase the number of colony-forming units of the fungus.C. albicans (obtained from L. Haley, Center for Disease Control, Atlanta, Ga.), was grown overnight in liquid Sabouraud medium. Cell viability was at least 97% as estimated by exclusion of trypan blue. The untreated cells, counted in a hemacytometer and then properly diluted, had a plating efficiency of 60 to 70%. That is, the number of colony-forming units on Sabourauddextrose-agar plates after 24 h of incubation at 37°C was 60 to 70% of the cell number counted in the hemacytometer. This plating efficiency was very reproducible in our laboratory and was also normally achieved in the Clinical Mycology Laboratory at Barnes Hospital. More prolonged incubation of the plates did not result in an increase in the number of colonies.To measure the effects of drug, cells were transferred to fresh liquid medium and exposed to the assayed compound for 1 h at 37°C with intermittent shaking. Cells incubated in concentrations of amphotericin B (AmB) lower than that causing detectable K+ leakage, formed more colonies in agar than did untreated cells (Fig. 1).The increase in colony-forming units was 20 to 50% (the mean from 5 experiments was 32 ± 6%), and the resulting plating efficiency was 80 to 95%.Similar increases in colony number were also observed when C. albicans was exposed in liquid medium to nontoxic concentrations of nystatin or filipin. The maximal increase in colony-forming units occurred at a concentration of 0.05 ,ug of nystatin per ml and 1.5 ,ug of filipin per ml. Fifty percent K+ leakage from C. albicans occurred at 0.2 jig of nystatin per ml and 8 ,g/ml of filipin per ml.We think that the increase in colony-forming units was caused by the portion of the polyene molecule which is responsible for the toxic effects. The evidence for this is that inactivation of AmB by exposure to visible light by a procedure previously described (9) or the addition of ergosterol to the cultures containing AmB decreased both of these effects proportionately.Differences in the temperature dependence of the nontoxic and toxic effects of the polyenes made us suspect that they had different mechanisms. AmB binds comparably to yeast at 37 and 2°C (7), but toxicity is greatly diminished at the lower temperature (1, 7). In the present experiments, 30% of intracellular K+ leaked ...

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Mode of Action of the Polyene Antibiotic Candicidin: Binding Factors in the Wall of Candida albicans

Cited by 23 publications

References 21 publications

Role of cell defense against oxidative damage in the resistance of Candida albicans to the killing effect of amphotericin B

Role of cell defense against oxidative damage in the resistance of Candida albicans to the killing effect of amphotericin B

Candicidin-producing Streptomyces support leaf-cutting ants to protect their fungus garden against the pathogenic fungus Escovopsis

Increase in colony-forming units of Candida albicans after treatment with polyene antibiotics

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