Fungal membranes

The plasma membrane of fungi has the typical lipid bilayer structure, with phosphatidylcholine, phosphatidylethanolamine, and ergosterol as major lipid con- 

Antifungal agent Total release of Percent of cells stained with 

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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... 

Uses Severe, systemic fungal Infxns oral cutaneous candidiasis Action Binds ergosterol in the fungal membrane to alter permeability Dose Adults Peds. Test dose 1 mg IV adults or 0.1 mg/kg to 1 mg IV in children then 0.25-1.5 mg/kg/24 h IV over 2-6 h (range 25-50 mg/d or qod). Total dose varies w/ indication PO 1 mL qid Caution [B, ] Disp Inj SE -1- K /Mg from renal wasting anaphylaxis reported, HA, fever, chills, n hrotox, -1- BP, anemia, rigors Notes -1- In renal impair pre-Tx w/ APAP antihistamines (Benadryl) X SE Interactions T Nephrotoxic effects W/ antineoplastics, cyclosporine, furosemide, vancomycin, aminoglycosides, T hypokalemia W/ corticost oids, skeletal muscle relaxants EMS May cause electrolyte imbalances, monitor ECG OD May effect CV and resp Fxn symptomatic and supportive... 

Inhibit synthesis of ergosterol, an important component of fungal membranes. 

React with ergosterol thus destroying fungal membrane integrity. 

Mechanism of Action A fungistatic antifungal that interferes with cytochrome P-450, an enzyme necessary for ergosterol formation. Therapeutic Effect Directly damages fungal membrane, altering its function. 

Mechanism of Action An antifungal that penetrates fungal cells and is converted to fluorouracil which competes with uracil interfering with fungal RNA and protein synthesis. Therapeutic Effect Damages fungal membrane. 

Fluconazole was designed following much earlier work on imidazole derivatives, which had been shown to inhibit a crucial step in biosynthesis of ergosterol, the essential sterol of the fungal membrane. Imidazoles were shown to be poorly effective in vivo because of rapid and extensive metabolism. Note the design features ... 

How do antibiotics act Some, like penicillin, block specific enzymes. Peptide antibiotics often form complexes with metal ions (Fig. 8-22) and disrupt the control of ion permeability in bacterial membranes. Polyene antibiotics interfere with proton and ion transport in fungal membranes. Tetracyclines and many other antibiotics interfere directly with protein synthesis (Box 29-B). Others intercalate into DNA molecules (Fig. 5-23 Box 28-A). There is no single mode of action. The search for suitable antibiotics for human use consists in finding compounds highly toxic to infective organisms but with low toxicity to human cells. 

Cholesterol is the most common steroid of mammalian membranes. It is formed biologically from lanosterol, as shown. Ergosterol is the most common steroid of fungal membranes. It differs from cholesterol by the presence of two additional double bonds that affect its three dimensional structure. Also shown are three so-called steroid hormones, andros-terone, estradiol, and testosterone. Note the presence of an aromatic A-ring in estradiol. 

Amphotericin B binds fungal membrane Ergosterol and inhibits its replication... 

Resistance Fungal resistance, though infrequent, is associated with decreased ergosterol content of the fungal membrane. 

Mode of action Ketoconazole interacts with C-14 a-demethylase (a cytochrome P-450 enzyme) to block demethylation of lanosterol to ergosterol, the principal sterol of fungal membranes Figure 34.4). This inhibition disrupts membrane function and increases permeability. Ketoconazole acts in an additive manner with flucytosine against Candida, but antagonizes amphotericin B s antifungal activity. 

Mode of action It inhibits the synthesis of fungal membrane ergosterol in the same manner as ketoconazole. 

Blocks lanosterol demethylation to ergosterol, thus disrupting fungal membrane integrity. 

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