In vitro activity of naftifine, a new antifungal agent

Georgopoulos, Apostolos P.; Petrányi, G; Mieth, H.; Drews, Jürgen

doi:10.1128/aac.19.3.386

Cited by 102 publications

(33 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…C. albicans A63, a clinical isolate, was maintained as a cell suspension stored in ampoules under liquid nitrogen as previously described (4). Cells were grown in shake culture at 30°C in Sabouraud dextrose broth (Merck) adjusted to pH 6.5.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Effect of the antimycotic drug naftifine on growth of and sterol biosynthesis in Candida albicans

Ryder¹,

Seidl²,

Troke³

1984

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Naftifine, a new antimycotic drug of the allylamine class, is a potent inhibitor of ergosterol biosynthesis in Candida albicans. Treated cells showed a dose-dependent drop in ergosterol content; the level was reduced by 60% at concentrations of >50 mg/liter, causing total inhibition of growth. This inhibition coincided with a heavy accumulation of the sterol precursor squalene. Radiolabeling experiments showed that the inhibition of sterol synthesis was complete within 10 min of exposure of cells to the compound. Control cells incorporated [14C]acetate into nonsaponifiable lipids composed primarily of ergosterol, whereas naftifinetreated cells accumulated only labeled squalene. When the drug was removed by washing cells thoroughly in 1% Tween 80, the accumulated squalene was further metabolized to ergosterol. A similar pattern of inhibition was observed in sterol biosynthesis from [14C]mevalonate in a cell-free system. At 50 mg/liter, naftifine gave >99% inhibition of sterol biosynthesis both in whole cells and in cell extracts of C. albicans. The primary action of naftifine appears to be the blocking of fungal squalene epoxidation.Naftifine is an allylamine antimycotic drug with activity against a wide range of pathogenic fungi, particularly dermatophytes both in vitro (4) and in vivo (12). In clinical trials, the compound proved very effective as a topical treatment for dermatomycoses (3). At higher concentrations, naftifine also has in vitro activity against Candida albicans (4) and may be clinically useful against this organism. As naftifine represents an entirely new chemical class of antifungal agents, it is important to establish the mode of action in a range of target organisms. Earlier work with the dermatophyte Trichophyton mentagrophytes and the yeast Candida parapsilosis (11) indicated that naftifine interferes with ergosterol biosynthesis by blocking squalene metabolism. In this report, we describe the activity of naftifine against C. albicans, using several experimental models designed to quantify the effects on ergosterol biosynthesis in comparison with the inhibition of cell growth.( Extraction of lipids. Cells were harvested by centrifugation and treated by saponification in 50% ethanol containing 15% KOH and 0.1% pyrogallol for 2 h under reflux. After the addition of 2 volumes of water, the nonsaponifiable lipid (NSL) was extracted three times with petroleum ether (40 to 60°C). The petrol extract was washed with water, dried over anhydrous sodium sulfate, filtered, and brought to dryness in a rotary evaporator. NSL was dissolved in cyclohexane and stored at -20°C in the dark. For quantitative analysis, a known amount of cholesterol was added as an internal standard before the extraction.Gas chromatography. Components of NSL were separated by using a Siemens gas chromatograph (Sichromat 1) with a glass column (110 by 0.6 cm) with 1% OV3 silicone on Chromosorb G (Supelco, Inc., Bellefonte, Pa.) in the stationary phase. The carrier gas was helium (23 ml/min), and the temperature range program was ...

show abstract

Section: Methodsmentioning

confidence: 99%

“…Naftifine is an allylamine antimycotic drug with activity against a wide range of pathogenic fungi, particularly dermatophytes both in vitro (4) and in vivo (12). In clinical trials, the compound proved very effective as a topical treatment for dermatomycoses (3).…”

mentioning

confidence: 99%

Effect of the antimycotic drug naftifine on growth of and sterol biosynthesis in Candida albicans

Ryder¹,

Seidl²,

Troke³

1984

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Naftifi ne (1) (see Table 2 ) is the fi rst antifungal agent, which blocks biosynthesis of ergosterol, the crucial component of all fungal cell membranes, by inhibiting epoxidation of squalene (Georgopoulos et al , 1981 ;Abe et al , 1994 (Georgopoulos et al , 1981 ;Ryder and Dupont , 1984 ;Kan et al , 1986 ). Currently it is used in the treatment of infections caused by pathogenic fungi, e.g., C. albicans and Trichophyton rubrum (Abe et al , 1994 ).…”

Section: Antimycotic Compoundsmentioning

confidence: 99%

Squalene monooxygenase – a target for hypercholesterolemic therapy

Belter¹,

Skupińska²,

Giel-Pietraszuk

et al. 2011

BCHM

View full text Add to dashboard Cite

Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafi ne, naftifi ne, butenafi ne) are in clinical use, whereas mammalian enzymes ' inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both suffi cient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future.

show abstract

“…The discovery of the antifungal activity of naftifine (Exoderil), which has been shown in vitro and in vivo against a variety of medically important species of fungi (3,6), led to intensive chemical and biological investigations of the structure-activity relationships of allylamine derivatives at the Sandoz Forschungsinstitut, Vienna, Austria (12,13). The antifungal activities of these compounds are based on the inhibition of fungal ergosterol biosynthesis at the point of squalene epoxidation (5,(8)(9)(10).…”

mentioning

confidence: 99%

Antifungal activity of the allylamine derivative terbinafine in vitro

Petrányi

Meingassner

Mieth

1987

Antimicrob Agents Chemother

Self Cite

231

View full text Add to dashboard Cite

Terbinafine, an allylamine derivative, represents the most effective of this new chemical class of antimycotic compounds. Under in vitro conditions, terbinafine proved to be highly active against dermatophytes (MIC range, 0.001 to 0.01 ,ug/ml), aspergilli (MIC range, 0.05 to 1.56 tig/ml), and Sporothrix schenckii (MIC range, 0.1 to 0.4 ,ug/ml) and also exerted good activity against yeasts (MIC range, 0.1 to >100 ,ig/ml). The growth of Malasseziafurfur was inhibited also (MIC range, 0.2 to 0.8 ,ig/ml). Terbinafine displays a primary fungicidal action against dermatophytes, other filamentous fungi, and S. schenckii. The type of action against yeasts is species dependent and can be primarily fungicidal (Candida parapsilosis) or fungistatic (Candida albicans). The in vitro activity of terbinafine is pH dependent and rises with increasing pH value.The discovery of the antifungal activity of naftifine (Exoderil), which has been shown in vitro and in vivo against a variety of medically important species of fungi (3, 6), led to intensive chemical and biological investigations of the structure-activity relationships of allylamine derivatives at the Sandoz Forschungsinstitut, Vienna, Austria (12,13). The antifungal activities of these compounds are based on the inhibition of fungal ergosterol biosynthesis at the point of squalene epoxidation (5,(8)(9)(10).The most active derivative of this new chemical class of antimycotics found so far is terbinafine (7, 14; G. Petranyi, J. G. Meingassner, and H. Mieth, 9th Int. Congr. Int. Soc. Hum. Anim. Mycol. (ISHAM), abstr. no. P1-27, 1985). In this report we describe the antifungal activity of this compound in vitro.(These data were presented in part at the 13th Interna- 5%, which were then stored as 1.5-ml portions in liquid nitrogen (2). The CFU of the stock cultures were determined after freezing. Appropriate dilutions were made with saline or broth before use.Malassezia strains were cultivated at 37°C in broth media by the method of Weary and Graham (15) by serial transfers.Assessment of antifungal activity. Serial dilution tests were used to determine the MICs of the test compounds for dermatophytes, molds, biphasic fungi, and yeasts. The MIC for Malassezia strains was evaluated by an agar dilution test. Activity against dermatophytes was assessed by an agar diffusion test also. Since it was found in radiolabeling studies that terbinafine tends to stick to plasticware, the assays were performed in glass.Serial dilution test. The MIC for filamentous fungi was determined in Sabouraud dextrose 2% broth (initial pH, 6.5). Malt extract broth (initial pH, 6.5; E. Merck) was used for yeasts.Glass tubes (16 by 160 mm) were filled with 0

show abstract

In vitro activity of naftifine, a new antifungal agent

Cited by 102 publications

References 1 publication

Effect of the antimycotic drug naftifine on growth of and sterol biosynthesis in Candida albicans

Effect of the antimycotic drug naftifine on growth of and sterol biosynthesis in Candida albicans

Squalene monooxygenase – a target for hypercholesterolemic therapy

Antifungal activity of the allylamine derivative terbinafine in vitro

Contact Info

Product

Resources

About