Ergosterol inhibition

A) Oral bioavailability is affected by first-pass hepatic metabolism Only third-generation cephalosporins cross the blood-brain barrier Procaine penicillin G is the most commonly used intravenous form of the antibiotic Renal tubular reabsorption of beta-lactams is inhibited by probenecid Nafcillin and ceftriaxone are eliminated mainly via biliary secretion The mechanism of antibacterial action of cephalosporins involves (A) Inhibition of the synthesis of precursors of peptidoglycans Interference with the synthesis of ergosterol Inhibition of transpeptidation reactions Inhibition of beta-lactamases Binding to cytoplasmic receptor proteins... 

Clotrimazole and other azole derivatives have a different mode of action than the polyenes, eg, amphotericin B. The latter biad to the ergosterol present ia the membranes of yeasts and fungi, but azole derivatives inhibit the cytochrome P-450 dependent biosynthesis of ergosterol (8—11). This inhibition not only results in a reduction of ergosterol, but also in an accumulation of C-14 methyl sterols. They disturb membrane permeabiUty, inhibit cell rephcation, and are basically responsible, in combination with the reduction of ergosterol levels, for the antifungal action. 

Miconazole. Miconazole nitrate [22832-87-7] (Fig. 2), the 1-phenethyl-imidazole derivative first described in 1969, interferes at low doses with the cytochrome P-450 dependent ergosterol biosynthesis in yeasts and fungi. The result is accumulation of C-14 methylated sterols on the one hand and reduction of the ergosterol levels in the membranes on the other hand (12). Analogous to clotrimazole, this leads to a disturbance in the membranes it results in inhibition of ceU repHcation, mycelium development (in C. albicans) and finally, ceU death. High concentrations of miconazole, which may be achieved with topical use, disturb the orientation of phosphoHpids in the membranes, which produces leaks (13). 

Like the a2ole derivatives, it inhibits the biosynthesis of ergosterol. However, naftifine [65472-88-0] does not inhibit the cytochrome P-450 dependent C-14-demethylase, but the epoxidation of squalene. Squalene epoxidase cataly2es the first step in the conversion of squalene via lanosterol to ergosterol in yeasts and fungi or to cholesterol in mammalian cells. The squalene epoxidase in C. albicans is 150 times more sensitive to naftifine, C2 H2 N, than the en2yme in rat fiver (15). Naftifine is available as a 1% cream. 

Plasma levels of 3—5 p.g/mL are obtained two hours after adraiinistration of 200 mg ketoconazole. No accumulation in the bloodstream was noted after a 30-wk treatment with this dose. The half-life is approximately eight hours. When ketoconazole is taken with meals, higher plasma levels are obtained. Distribution studies using radioactive ketoconazole in rats show radioactivity mainly in the Hver and the connective tissue. Radioactivity is also present in the subcutaneous tissue and the sebaceous glands. After one dose of 200 mg in humans, ketoconazole is found in urine, saUva, sebum, and cenimen. Like miconazole, the mode of action is based on inhibition of the cytochrome P-450 dependent biosynthesis of ergosterol. This results in disturbed membrane permeabiUty and membrane-bound enzymes (8,10,23,25). 

Ag-isomerase leading to depletion of ergosterol and accumulation of an unplanar sterol ignosterol. With the inhibition of two steps in the same pathway, a natural synergistic effect is built into the molecule so that the risk of appearance of resistant mutants is low and efficacy high. 

Cytoplasmic membrane Polymyxins Polyenes Imidazoles and triazoles Naftidine Disrupt bacterial membranes Disrupt fungal membranes Inhibit ergosterol synthesis Inhibits ergosterol synthesis Bind to LPS and phospholipids Bind preferentially to ergosterol Pathway not in mammalian cells Pathway not in mammalian cells... 

This synthetic allylamine derivative inhibits the enzyme squalene epoxidase at an early stage in fungal sterol biosynthesis. Acting as a structural analogue of squalene, naffidine causes the accumulation of this unsaturated hydrocarbon, and a decrease in ergosterol in the fungal cell membrane. 

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

The inhibitory effects of in vitro sterol addition (21) showed large percentage kills (83% and 91% respectively). The in vitro addition of ergosterol (10.1 mM) to P brevis cell cultures with Filipin (1.5 mM) showed complete inhibition of the cytolytic effect. Ergosterol (10.1 mM) added to P. brevis cell cultures with cell extract showed a 10% reduction in cell mortality. The addition of ergosterol alone (control) showed no cytolytic effect at the experimental concentration (10.1 mM). 

The answer is a. (Hardman, p 1180. Katzung, pp 817—819J Fluconazole indirectly inhibits ergosterol synthesis. It inhibits cytochrome P4.50, which is a key enzyme system for cytochrome P4.5O-dependent sterol 14-a-demethylase. This leads to accumulation of 14-a-sterols, resulting in impairment of the cytoplasmic membrane. 

Synthesis-Directing Structure-Activity Relationships of Some Fungicides Inhibiting Ergosterol Biosynthesis... 

Although termed "SI" or "EBI" compounds, the latter referring to ergosterol biosythesis inhibitors, these compounds do not all inhibit ergosterol biosynthesis at the same metabolic site (Fig. 2). For instance, the fungicide tridemorph, unlike most EBI compounds, does not inhibit demethylation at C-14 but rather it apparently prevents the A A isomerization resulting in the accumulation of A containing sterols in treated cells (3). 

The schematic presentation of ergosterol biosynthesis and EBI sites of inhibition is available in references (Siegel [5] Kato [6]) and only that segment directly related to the interests of this report will be presented here (Figure 4). 

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