Antifungals are compounds that inhibit or block the growth of fungi, which are eukaryotic unicellular or multicellular organisms. Some fungi that cause disease in humans are yeasts, molds, and biphasic (dimorphic) fungi. The mechanisms of antifungal action include inhibition of fungal membrane and cell wall synthesis, obstruction of fungal nucleic acid synthesis, modification of the fungal cell membrane, and inhibition of fungal mitosis. Four major classes of antifungals are azoles, echinocandins, polyenes and pyrimidine analogs. Echinocandins and polyenes were discovered by screening of natural products.
Ergosterol is the major component of the fungal cell membrane and contributes to a variety of cellular functions. Azoles inhibit the activity of cytochrome P450-dependent sterol 14α-demethylase (CYP51) which converts lanosterol to ergosterol in the cell membrane, thereby inhibiting fungal growth and replication. Azoles are cyclic organic molecules and mainly can be classified into two groups based on the number of nitrogen atoms in a ring: imidazoles (miconazole, oxiconazole, econazole, ketoconazole, tioconazole, and clotrimazole) with two nitrogen atoms in the azole ring; and triazoles (posaconazole, itraconazole, terconazole, and voriconazole and fluconazole) which contain three nitrogen atoms in the ring. In addition to Azoles, other ergosterol biosynthesis inhibitors are allylamines, thiocarbamates, and morpholines. Allylamines (e.g., terbinafine) and thiocarbamates (e.g., tolnaftate) inhibit the ERG1 gene of ergosterol biosynthesis, while morpholines (e.g., fenpropimorph and amorolfine) inhibit the ERG24 and ERG2 genes of ergosterol biosynthesis.
Polyenes are a class of broad-spectrum antifungals with a cyclic amphiphilic macrolide substructure. Due to their amphiphilic structure, polyenes bind to ergosterol and form pores in the cell membrane of fungi. Pore formation promotes disruption of the cell membrane, the leakage of the cytoplasmic contents and oxidative damage to result in fungal cell death. Polyenes mainly include amphotericin B (AmpB), natamycin (pimaricin) and nystatin. They are natural products and can be isolated from the cultivation broths of Streptomyces noursei, S. natalensis and S. nodosum, respectively. Polyenes are used generally against Cryptococcus, Candida, and Aspergillus species.
Echinocandins that target fungi cell wall include caspofungin, micafungin, and anidulafungin. Echinocandins are noncompetitive inhibitors of β-1-3-glucan synthase, which is critical to the synthesis of β-1-3-glucan. Inhibition of this enzyme results in disruption of the structure of cell walls, causing fungal osmotic instability and cells death.
Pyrimidine analogs are the synthetic structural analogs of nucleotide cytosine, including 5-fluorocytosine (5-FC) and 5-fluorouracil (5-FU). 5-FC is transported into susceptible fungi by cytosine permease, and then 5-FC is converted to the downstream product 5-FU by cytosine deaminase to obtain antifungal activity including interferes with pyrimidine metabolism, as well as RNA/DNA and protein synthesis.
Amerigo Scientific offers a variety of antifungals, including disruptors of cell membranes, inhibitors of sterol synthesis, mitosis inhibitors, DNA synthesis inhibitors and cell wall synthesis inhibitors.
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