Antifungals, squalene

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) ... 

Mechanism of Action A fungicidal antifungal that inhibits the enzyme squalene ep-oxidase, thereby interfering with fungal biosynthesis. Therapeutic Effect Results in death of fungal cells. 

It is a synthetic allylamine derivative, which exerts its antifungal effect by inhibiting squalene epoxidase leading to deficiency of ergosterol and corresponding accumulation of squalene which causes fungal cell death. 

Naftifine hydrochloride and terbinafine (Lamisil) are allylamines that are highly active against dermatophytes but less active against yeasts. The antifungal activity derives from selective inhibition of squalene epoxidase, a key enzyme for the synthesis of ergosterol (see Figure 48-1). 

Nowicki and Bara ska-Rybak (2007) studied the protective effect of shark liver oil. They observed a significant protection against bacterial and fungal infections by shark liver oil treatment which contains mostly squalene and alkylglycerol. Further, this treatment showed improved effects on xerosis and skin lesion-induced atopic dermatitis. This antibacterial and antifungal effect could be accounted for the high-squalene-including composition of the shark liver oil however, detailed studies are needed to be carried out for reputed activity of squalene as an anti-infectant. 

Zaragozic Acids The zaragozic acids (squalestatins) are a class of competitive inhibitors of mouse, rat, and HepG2 squalene synthases, which also display antifungal activity [104]. The characteristic structural feature of this family of natural products is its highly oxygenated core. 

G Petranyi, NS Ryder, A Stutz. Allylamine derivatives new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science 224 1239-1241,1984. 

Inhibitors of squalene epoxidase are used in antifungal drugs to treat athlete s foot, jock itch, ringworm, and nail infections. The drug Tinactin (tolnaf-tate) inhibits squalene epoxidase, which blocks the synthesis of the steroids the fungus needs to make its cell membrane. The defective cell membrane kills the fungus. 

Antifungal Fungal squalene epoxidase Terbinafine, naftifine... 

Since ergosterol is used in the formation of the leishmanial cell membrane, inhibition of ergosterol biosynthesis has been considered as a useful target for chemotherapeutic attack. Allylamines (eg. terbinafine) and imidazole antifungals (eg. ketoconazole) have been found to interfere with different steps in the biosynthetic pathway of C28 sterols in leishmania and fungi. Allylamines inhibit the microsomal squalene 2,3-epoxidase and, therefore, inhibit the synthesis of squalene epoxide, the precursor of lanosterol. Imidazoles, on other hand, inhibit cytochrome P-450 dependent C-14 demethylation of lanosterol leading to decreased or no synthesis of ergosterol [30]. 

Naftifine, a broad-spectrum antifungal agent, is a synthetic allylamine derivative that interferes with sterol biosynthesis by inhibiting the enzyme squalene 2,3-epoxidase. This inhibition of enzyme activity results in decreased amounts of sterols, especially ergosterol, and a corresponding accumulation of squalene in the cells. 

Isolation and structure elucidation of a novel family of cholesterollowering constituents, viridiofungins A (37), B (38) and C (39), from Trichoderma viride, were reported and they were potent in vitro inhibitors of squalene synthase (IC50 values = 41.6, 19.3 and 0.29 pg/mL) in HepG2 cells. These compounds also showed broad-spectrum and potent antifungal activities [65,66]. 

Bisabosqual A (40) was isolated from the culture broth of Stachybotrys sp. RF-7260. Its structurally related compounds, bisabosquals B (41), C (42) and D (43) were also isolated from Stachybotrys ruwenzoriensis RF-6853. All the bisabosqual compounds inhibited squalene synthases of microbial and mammalian origins. Bisabosqual A showed significant inhibitory activity against the microsomal squalene synthases from HepG2 cells and rat liver. Its IC50 values were 0.95 and 2.5 p g/mL, respectively. Bisabosqual A also showed broad-spectrum antifungal activity in vitro. Bisabosqual C exhibited inhibitory activities similar to those of bisabosqual A [67, 68]. 

CJ-15,183 (44) has been isolated from the fermentation culture of the fungus, Aspergillus aculeatus CL38916 as a squalene synthase inhibitor. The compound potently inhibited rat liver and human squalene synthases. In addition, it showed antifungal activities against filamentous fungi and yeast. The structure was elucidated to be an aliphatic tetracarboxylic acid compound consisting of an alkyl y-lactone, malic acid and isocitric acid moieties by spectroscopic analyses [69]. 

A schematic of fungal ergosterol biosynthesis starting from squalene is shown in Figure 40.1. The biosynthetic pathway has been simplified to emphasize steps important to the action of currently employed antifungal drugs. The last nonsteroidal precursor to both ergosterol and cholesterol is the hydrocarbon squalene. Squalene is converted to squalene epoxide by the enzyme squalene epoxidase. Squalene epoxide is then cyclized to lanosterol, the first steroid in the biosynthetic pathway. The... 

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