Relationship between antifungal activity and inhibition of sterol biosynthesis in miconazole, clotrimazole, and 15-azasterol

Taylor, F. R.; Rodriguez, Russell J.; Parks, Leo W.

doi:10.1128/aac.23.4.515

Cited by 31 publications

(13 citation statements)

References 32 publications

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“…Scott et al (259) demonstrated a reduction in ergosterol levels in T. mentagrophytes following exposure to miconazole as well. In contrast, Taylor et al (299) have presented data indicating that inhibition of C-14 demethylation is not a fungicidal event. They have proposed that direct membrane damage to the fungus may be the key antifungal activity of miconazole and other imidazole drugs.…”

Section: Clotrimazolementioning

confidence: 88%

Overview of medically important antifungal azole derivatives

1988

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Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death. The selection of chemotherapeutic agents useful for the treatment of fungal infections is small. In this overview, a major chemical group with antifungal activity, the azole derivatives, is examined. Included are historical and state of the art information on the in vitro activity, experimental in vivo activity, mode of action, pharmacokinetics, clinical studies, and uses and adverse reactions of imidazoles currently marketed (clotrimazole, miconazole, econazole, ketoconazole, bifonazole, butoconazole, croconazole, fenticonazole, isoconazole, oxiconazole, sulconazole, and tioconazole) and under development (aliconazole and omoconazole), as well as triazoles currently marketed (terconazole) and under development (fluconazole, itraconazole, vibunazole, alteconazole, and ICI 195,739).

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Section: Clotrimazolementioning

confidence: 88%

Overview of medically important antifungal azole derivatives

1988

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“…This idea is supported by several previous observations and comments. Taylor et al (14) showed that the azoles were still inhibitory toward sterol auxotrophic mutants of S. cerevisiae. Odds (11) also states, "most azoles are able to prevent or greatly perturb hyphal growth of C. albicans.…”

mentioning

confidence: 99%

Farnesol Biosynthesis in Candida albicans : Cellular Response to Sterol Inhibition by Zaragozic Acid B

Hornby

Kebaara

Nickerson

2003

Antimicrob Agents Chemother

108

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The dimorphic fungus Candida albicans produces farnesol as a quorum-sensing molecule that regulates cellular morphology. The biosynthetic origin of farnesol has been resolved by treating these cells with zaragozic acid B, a potent inhibitor of squalene synthase in the sterol biosynthetic pathway. Treatment with zaragozic acid B leads to an eightfold increase in the amount of farnesol produced by C. albicans. Furthermore, C. albicans cell extracts contain enzymatic activity to convert [ 3 H]farnesyl pyrophosphate to [ 3 H]farnesol. Many common antifungal antibiotics (e.g., zaragozic acids, azoles, and allylamines) target steps in sterol biosynthesis. We suggest that the fungicidal activity of zaragozic acid derives in large part from the accumulation of farnesol that accompanies the inhibition of sterol biosynthesis.

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“…If growth inhibition were simply due to the depletion of ergosterol, strain JR4 would be as susceptible or perhaps more susceptible to fenpropimorph than the wild-type strain is. It has been demonstrated that 14-methylfecosterol can satisfy the bulk membrane requirements, but not the structurally specific sparking function, which can be fulfilled by the small amounts of ergosterol that are produced (19,21).…”

Section: Fp13c (Fen] Fen2 Leu2 Ura3 His4) and Fp13d (Fen] Fen2mentioning

confidence: 99%

“…Studies with S. cerevisiae have demonstrated that 15-azasterol inhibits the A' isomerase and C-14-reductase of the ergosterol pathway, similar to fenpropimorph, which results in the production of ignosterol (7). Thus, it was of interest to It has been shown previously (21) that strain JR4 (erg3 ergll), which carres mutations in C-5-desaturase and C-14-demethylase, respectively, is resistant to the growth inhibitory effects of 15-azasterol. Because of these mutations in the sterol pathway, 14-methylfecosterol [14a-methyl-ergosta-8,24(28)-dien-3p-ol] is the major sterol produced in this strain (21).…”

Section: Fp13c (Fen] Fen2 Leu2 Ura3 His4) and Fp13d (Fen] Fen2mentioning

confidence: 99%

“…Thus, it was of interest to It has been shown previously (21) that strain JR4 (erg3 ergll), which carres mutations in C-5-desaturase and C-14-demethylase, respectively, is resistant to the growth inhibitory effects of 15-azasterol. Because of these mutations in the sterol pathway, 14-methylfecosterol [14a-methyl-ergosta-8,24(28)-dien-3p-ol] is the major sterol produced in this strain (21). Since fenpropimorph inhibits the C-14-reductase enzyme directly after the block in JR4 (ergl l), we reasoned that if the accumulation of ignosterol is linked to the growth inhibition of the wild-type strain, this double mutant should be resistant to fenpropimorph and other morpholines.…”

Section: Fp13c (Fen] Fen2 Leu2 Ura3 His4) and Fp13d (Fen] Fen2mentioning

confidence: 99%

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Physiological effects of fenpropimorph on wild-type Saccharomyces cerevisiae and fenpropimorph-resistant mutants

Lorenz

Parks

1991

Antimicrob Agents Chemother

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Fenpropimorph-resistant mutants of Saccharomyces cerevisiae were isolated by a gradient selection procedure. The mutants were cross-resistant to other morpholines (fenpropidin, dodemorph, tridemorph) and 15-azasterol, but were susceptible to azoles (miconazole, clotrimazole, ketoconazole) and nystatin. In the absence of fenpropimorph, the major sterol produced by the mutants and the parental strain was ergosterol. In the presence of fenpropimorph, ignosterol (ergosta-8,14-dien-3j-ol) was the major sterol produced by the mutants and the parental strain. The resistance to fenpropimorph involves two recessive genes, each of which allows a semiresistance, when they are isolated apart from one another. Strain JR4 (erg3 ergll), which produces 14-methylfecosterol [14kx-methyl-ergosta-8,24(28)-dien-33-ol] as the major sterol in the presence or absence of fenpropimorph, was also found to be resistant to the drug. The growth inhibitory effect of fenpropimorph on wild-type cells appears to be linked to the production of ignosterol. The uptake of exogenous sterol by wild-type cells was greatly enhanced in the presence of fenpropimorph. The growth inhibition caused by fenpropimorph could only be overcome with bulk levels of exogenous C-5,6-unsaturated sterols.The morpholine fenpropimorph, 4-{3-[4-(1,1-dimethylethyl) phenyl]-2-methylpropyl}-2,6(cis)-dimethyl-morpholine, has been successfully used in agriculture against fungi that cause powdery mildew of cereals, cereal rusts, and leaf blotch of barley (3). This antifungal agent inhibits two enzymes of the ergosterol biosynthetic pathway. Experiments conducted in vivo and in vitro have revealed that the A'7 isomerase of Saccharomyces cerevisiae is inhibited at lower concentrations of fenpropimorph than is the C-14-reductase, while higher concentrations inhibit both enzymes (1, 13). As a consequence, exposure of susceptible fungal cultures to fenpropimorph leads to the accumulation of sterolic intermediates such as ergosta-8,14,24(28)-trienol, ergosta-8,14,22-trienol, ergosta-8,24(28)-dienol (fecosterol), ergosta-8,14-dienol (ignosterol), and ergosta-8-enol (1, 14).We have shown that sterols mediate at least four physiological functions in S. cerevisiae (17,19). One of these, the "sparking function," is essential and has an absolute requirement for C-5,6-unsaturated sterols. In wild-type S. cerevisiae, this requirement is satisfied by ergosterol. A recent study suggested that the growth inhibitory effect of fenpropimorph is not due to the accumulation of sterol intermediates but is related to the depletion of ergosterol (12). Although no field pathogen or laboratory strain has been reported with a significantly decreased susceptibility to fenpropimorph (1), we reasoned that some mutants resistant to the antifungal agent might have an altered sparking function such that a C-5,6 unsaturation is not required. Resistant mutants could help us probe the biochemical events in the sparking function.In this study, we report the isolation of new fenpropimorph-resistant strains of S. cer...

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Relationship between antifungal activity and inhibition of sterol biosynthesis in miconazole, clotrimazole, and 15-azasterol

Cited by 31 publications

References 32 publications

Overview of medically important antifungal azole derivatives

Overview of medically important antifungal azole derivatives

Farnesol Biosynthesis in Candida albicans : Cellular Response to Sterol Inhibition by Zaragozic Acid B

Physiological effects of fenpropimorph on wild-type Saccharomyces cerevisiae and fenpropimorph-resistant mutants

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