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20 Cards in this Set
- Front
- Back
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Antifungal targets
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Cell Wall
Plasma Membrane DNA Synthesis Mitotic Spindle Ergosterol Synthesis |
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Inhibitors of Fungal Membrane Stability
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Polyenes:
Amphotericin B Nystatin |
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Polyenes mechanism of action
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Binds ergosterol forming pores that alter fungal membrane permeability.
Allows for leakage of cellular contents. |
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Polyene resistance
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Decreased ergosterol content of fungal cells
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Amphoteracin B selectivity and toxicity
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500X more affinity for ergosterol than choleterol.
At high conc. interaction with cholesterol leads to formation of membrane pores |
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Target intermediates of ergosterol biosynthesis
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Squalene Epoxidase
14α-Steroldemthylase |
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Inhibitors of Squalene Epoxidase
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Allylamines
Benzylamines |
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Allylamine/Benzylamine Mechanism of action
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Inhibitoin of Squalene Epoxidase causes decreased production of ergosterol leading to destabalization of membrane and accumulation of toxic squalene
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Inhibitors of 14α-Steroldemethylase
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"Azoles":
Imidazoles Triazoles |
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Imidazole/Triazole mechanism of action
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Decrease ergosterol synthesis > Accumulation of 14α-methylsterols > causes disruption of tightly packed acyl chains of phospholipids
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Imidazole/Triazole Toxicity and Resistance
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Azoles are also selecive for hepatic P450 enzyme
Resistance is by P450 mutation or Multidrug Efflux pump |
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Inhibitors of β(1,3)-Glucan Synthase
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Echinocandins:
Caspofungin Micafungin Anidulafungin |
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Echinocandin mechanism of action
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Non-competitively inhibits β(1,3)-D-glucan > causes disruption of cell wall integrity
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Inhibitors of thimidylate (nucleic acid) synthesis
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Flucytosine
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Flucytosine mechanism of action
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Inhibition of thimidylate synthase blocks converstion of dUMP to dTMP > lack of dTMP ihibits DNA synthesis.
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Flucytosine specificity
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Flucytosine is taken up by fungal cells by cytosine-specific permeases. Mamalian cells lack these transporters
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Flucytosine toxicity and resistance
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Flucytosine can br converted into 5-fluorouracil (toxic antineoplastic compound) by intesinal flora.
Resistance is by mutation in cytosine permease or cytosine deaminase |
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Inhibitors of Mitosis
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Griseofulvin
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Griseofluvin mechanism of action
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Binds tubulin and microtubule associated proteins (MAP's) disrupting the formatino of the mitotic spindle
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Griseofluvin specificity
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Higher affinity for fungal tubulin > lower concentration for fungal mitosis inhibition
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