Disruption of Fungi Cell Membranes by Polyenes, Azoles, Allylamines, Amino Acids and Peptides

Abstract

The fungal cell membrane is one of the targets for some groups of antifungal agents: the polyenes, lipodepsinonapeptides, amino acids and other peptides, which interferes with the structural integrity of the lipid bilayer. Polyene antifungals show effectiveness against sterol-containing organisms by interacting directly with the fungal ergosterol. Amphotericin B exhibits activity against most species of Candida, Cryptococcus neoformans, most Aspergillus sp., hyaline molds, Penicillium, Paecilomyces, and Scopulariopsis, dimorphic fungi including Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and Paracoccidioides brasiliensis. Nystatin binds to sterols in the cell membrane of yeasts resulting in electrolyte leakages. Statins are competitive inhibitors of HMG-CoA reductase, which is involved in the ergosterol synthesis. The azoles specifically inhibits the cytochrome P450 enzyme CYP51, resulting in interruption of membrane synthesis, depletion of ergosterol leading to an increase in toxic methylated sterol precursors in the cell membrane. The morpholines are synthetic antifungals and inhibits the reductase and isomerase enzymes in ergosterol biosynthesis triggering accumulation of dimethyllanosterol and depletion of ergosterol. Aureobasidins are highly lipophilic and act by inhibiting inositol phosphoceramide (IPC) synthase, critical in fungal sphingolipid biosynthesis thereby depleting essential sphingolipids in the fungal cells. The lipopeptide iturin acts by increasing membrane permeabilization in fungal cell. Lipodepsinonapeptides produced by Pseudomonas syringae interacts with the fungal cell membrane by pore formation resulting in fatal electrolytic leakage. Syringomycins form ion channels in the fungal plasma membrane employing a novel sphingolipid-modulated channel formation mechanism while Pseudomycin A alters several membrane functions like membrane potential, protein phosphorylation, H1-ATPase activity, and cation transport fluxes.