The Development Of Resistance By Candida Species To Polyene Antibiotics In Vitro

Athar, M.A.; Winner, Hannes

doi:10.1099/00222615-4-4-505

Cited by 116 publications

(36 citation statements)

References 18 publications

(4 reference statements)

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“…Thus, binding alone of this multifunctional lipid should be sufficient for killing yeast cells. Fourth, structural modification and/or decreased expression of ergosterol via mutations in the sterol biosynthesis pathway substantially diminish fungal pathogenicity in vivo (27). Therefore, a primary mechanism involving direct ergosterol binding and sequestration would help explain why clinically significant resistance to AmB is so rare.…”

Section: Small Molecules | Protein-like Functions | N-methyliminodiacmentioning

confidence: 99%

Amphotericin primarily kills yeast by simply binding ergosterol

Gray

Palacios

Dailey

et al. 2012

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

488

408

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Amphotericin B (AmB) is a prototypical small molecule natural product that can form ion channels in living eukaryotic cells and has remained refractory to microbial resistance despite extensive clinical utilization in the treatment of life-threatening fungal infections for more than half a century. It is now widely accepted that AmB kills yeast primarily via channel-mediated membrane permeabilization. Enabled by the iterative cross-coupling-based synthesis of a functional group deficient derivative of this natural product, we have discovered that channel formation is not required for potent fungicidal activity. Alternatively, AmB primarily kills yeast by simply binding ergosterol, a lipid that is vital for many aspects of yeast cell physiology. Membrane permeabilization via channel formation represents a second complementary mechanism that further increases drug potency and the rate of yeast killing. Collectively, these findings (i) reveal that the binding of a physiologically important microbial lipid is a powerful and clinically validated antimicrobial strategy that may be inherently refractory to resistance, (ii) illuminate a more straightforward path to an improved therapeutic index for this clinically vital but also highly toxic antifungal agent, and (iii) suggest that the capacity for AmB to form proteinlike ion channels might be separable from its cytocidal effects.small molecules | protein-like functions | N-methyliminodiacetic acid boronates

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Section: Small Molecules | Protein-like Functions | N-methyliminodiacmentioning

confidence: 99%

Amphotericin primarily kills yeast by simply binding ergosterol

Gray

Palacios

Dailey

et al. 2012

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

488

408

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“…Individual organisms of the mutant strains each possess about 2 to 3 times as much ergosterol as do those of the parent (see Table I); thus, these mutants are unlike both the nys-3 mutants of Saccharomyces cerevisiae (Woods, 1971) and the 'trained ' Candida strains (Athar & Winner, 1971) which appear to be deficient in ergosterol. Nys-I mutants of S. cerevisiae (which are more resistant than nys-3 mutants; Woods & Ahmed, 1968) possess a new sterol (Woods, 1971) in addition to ergosterol, and the Candida albicans mutant strains YL and YS seem to be analogous to these.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have indicated that polyene resistance may be associated with altered sterol patterns in Candidu spp. (Athar & Winner, 1971), quantitatively, and in Saccharomyces cerevisiae (Thompson, Starr & Parks, 1971 ;Woods, 197r), quantitatively and qualitatively. Following the recent isolation (Hamilton-Miller, I 972) of a new type of polyene-resistant Candida albicans mutant (mutagen-induced), the sterol contents of such mutants were compared with that of the parent strain.…”

mentioning

confidence: 99%

Sterols from Polyene-resistant Mutants of Candida albicans

Hamilton‐Miller

1972

Journal of General Microbiology

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I N T R O D U C T I O NPolyene antibiotics act by combining with sterols in the membrane of susceptible organisms, and thereby affect permeability. Recent studies have indicated that polyene resistance may be associated with altered sterol patterns in Candidu spp. (Athar & Winner, 1971), quantitatively, and in Saccharomyces cerevisiae (Thompson, Starr & Parks, 1971 ; Woods, 197r), quantitatively and qualitatively. Following the recent isolation (Hamilton-Miller, I 972) of a new type of polyene-resistant Candida albicans mutant (mutagen-induced), the sterol contents of such mutants were compared with that of the parent strain. M E T H O D SA clinically isolated Candida albicans strain (799-S) was treated with N-methyl-"nitro-N-nitrosoguanidine, and four polyene-resistant mutants, 7 9 9 -x~, -XS, -YL and -YS, were isolated (Hamilton-Miller, I 972). Organisms were grown on Sabouraud agar contained in 14 cm Petri plates (two plates for each strain), inoculated with 2 ml amounts of Sabouraud broth overnight cultures and incubated at 37 "C for 48 h. Organisms were washed off the plates, washed with water and then homogenized in an equal volume of water (2 to 3.5 ml); I ml amounts of the resulting suspensions were removed for dry weight determinations, and 2 ml amounts were saponified in ethanolic KOH and analysed for sterols, as described by Breivik & Owades (1957). This procedure was followed three times with each of the five strains. Spectra were recorded by using a Unicam SP 800 spectrophotometer. R E S U L T SAs shown in the Table I , strain XL contained significantly more ergosterol than the parentwhile differences between the other three strains and the parent were not significant, as far as ergosterol content/mg dry wt is concerned.Qualitatively, the absorption spectra of hexane extracts of all five strains were virtually identical in the region 300 to 265 nm, and showed the characteristic three-peaked spectrum of ergosterol (Ah,,, at 293, 282 and 271 nm). The extracts from the parent strain and from strains XL and xs showed no other peaks, but those from strains YL and Y S had considerable absorption in the region 255 to 230 nm, with a plateau between 240 and 230 nm having E = 1-5 x E282 nm. The spectrum of these two extracts thus closely resembles that of the nys-I a mutant of Saccharomyces cerevisiae described by Woods (1971).

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“…These studies indicated that polyene resistance is associated with altered sterol patterns (Athar and Winner, 1971;Hamilton-Miller, 1972;Subden et al, 1977;Hitchcock et al, 1987). In vitro studies showed the sterol metabolism of polyene-resistant mutant C. albicans was quantitatively and qualitatively different then sensitive parent strains.…”

mentioning

confidence: 96%

“…It should be noted that resistant fungi and yeast cultures showed decreased growth rate, reduced production of germ tubes, slower production of chlamydospores, reduced suspension stability, and reduced pathogenicity when compared to sensitive parent strains (Athar and Winner, 1971). " The quantitative and qualitative alterations in the sterols of the fungal membrane responsible for reduced affinity to polyene antibiotics, seem at the same time to lower the fitness of mutants which are resistant to these antibiotics" (Dekker and Gielink, 1979).…”

mentioning

confidence: 99%

Comparative Study of a Semisynthetic Derivative of Natamycin and the Parent Antibiotic on the Spoilage of Shredded Cheddar Cheese

Suloff

Marcy

Hackney

et al. 2003

Journal of Food Protection

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The polyene macrolide antibiotic natamycin (Antibiotic A-5283) is commonly used to retard the growth of surface molds on various cheese varieties. Natamycin is commonly applied to the surface of cheese by dipping or spraying, using an aqueous dispersion containing 200 to 300 ppm of the additive. The large molecular weight of natamycin, 666 g/mol, and conjugated double bond structure causes it to be extremely insoluble in water and most food grade solvents. The inability to apply natamycin in true solution creates void non-treated areas on the food surface. These non-treated areas promote the growth of fungal organisms.A water soluble N-alkyl semisynthetic derivative of natamycin was synthesized by the Michael addition reaction of the parent with a N-substituted malemide. A comparative study investigating the effectiveness of the semisynthetic derivative of natamycin and the parent antibiotic in suppressing mold growth on one month aged shredded Cheddar cheese modified atmosphere packaged (MAP) was performed. A 20 ppm natamycin treatment effectively suppressed visible mold growth (<10 4 CFU/g) in MAP samples for up to 30 days after opening. The 20 ppm semisynthetic derivative performed similarly to the 10 ppm natamycin treatment in retarding mold growth. Visible mold growth did not occur for these treatments in MAP samples until 20 days after opening. Analysis of storage conditions revealed that an outgrowth of mold in shredded cheese occurred in MAP packages stored longer than 15 days. This bloom in mold growth was attributed to the degradation of natamycin and the semisynthetic derivative throughout storage.The stability and degradation of natamycin and the derivative were monitored throughout the study. Antibiotic concentration on the cheese surface was quantified by molecular absorption spectrometry. Results from this study showed, heavily contaminated samples caused the rate and loss of natamycin and the derivative to increase. Antibiotic concentration decreased at a similar rate in MAP and open package conditions. Natamycin and derivative were found to have similar degradation properties.iii DEDICATION This thesis is dedicated to my wife, Amy Lynn Suloff. I cannot express in words the love and support Amy provided during this project. For these endearing qualities, and so many more I want to thank her. iv ACKNOWLEDGMENTS

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The Development Of Resistance By Candida Species To Polyene Antibiotics In Vitro

Cited by 116 publications

References 18 publications

Amphotericin primarily kills yeast by simply binding ergosterol

Amphotericin primarily kills yeast by simply binding ergosterol

Sterols from Polyene-resistant Mutants of Candida albicans

Comparative Study of a Semisynthetic Derivative of Natamycin and the Parent Antibiotic on the Spoilage of Shredded Cheddar Cheese

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