Antifungals - Dr.Stahelin - 8 questions Flashcards
Be able to describe which steps (enzymes) are inhibited by the allylamines and the azole antifungals in ergosterol synthesis.
-Allylamines: inhibit the squalene epoxidase enzyme and prevent the production of ergosterol. This leads to an accumulation of squalene in the fungal cell which is toxic and leads to cell death
Azole: Inhibit 14 alpha demethylase (CYP450 enzyme) and block convertion of lanosterol to ergosterol which leads to accumulation of lanosterol which is toxic to the cell and eventually causes cell death
Be able to name the family they belong to, recognize the general structure, discuss the mechanisms of action, the basis for selective inhibition of fungi:
* Amphotericin B, Nystatin
Family:Polyenes
- LOOK at structure – lipophilic bottom and hydrophilic top
- MOA: bind to ergosterol in the cell membranes and lead to leakage of cell and cell death
- Basis for selective inhibition of fungi: Mycoamine present on structure is required for binding to ergosterol
- Lipid formulation reduces nephrotoxicity
- Nystatin is the topical formulation commonly used for superficial fungal infections
Be able to name the family they belong to, recognize the general structure, discuss the mechanisms of action, the basis for selective inhibition of fungi:
* Terbinafine
- Family: Allylamines
- LOOK AT STRUCTURE:
- MOA: inhibit squalene epoxidase which disrupts ergosterol synthesis, leads to build up of squalene which is extremely toxic to fungal cells
- Basis for selective inhibition of fungi: 2,500 fold selectivity for fungal enzyme compared to mammalian enzyme
Be able to name the family they belong to, recognize the general structure, discuss the mechanisms of action, the basis for selective inhibition of fungi:
* Ketoconazole, Itraconazole, Fluconazole, Voriconazole, Isavuconazole
- Family: Azoles
- LOOK AT STRUCTURE: 5-member aromatic ring
- MOA: inhibit 14 alpha demethylase (CYP450) and inhibit the convertion of lanosterol to ergosterol – leads to accumulation of toxic sterol and cell death
- Basis for selective inhibition of fungi: humans use same enzyme to make cholesterol but fungal enzyme is more sensitive but it still leads to inhibition of CYP450s in mammalian cells (drug interations)
Be able to name the family they belong to, recognize the general structure, discuss the mechanisms of action, the basis for selective inhibition of fungi:
* Oteseconazole
- Family: azole
- LOOK AT STRUCTURE:
- MOA: Selective inhibitor of the fungal enzyme CYP51 (a 14 alpha-demethylase)
- Basis for selective inhibition of fungi: low events of adverse events due to good selectivity for fungal vs human
Be able to name the family they belong to, recognize the general structure, discuss the mechanisms of action, the basis for selective inhibition of fungi:
* Caspofungin, Micafungin, Anidulafungin
- Family: Echinocandins
- LOOK AT STRUCTURE:
- MOA: Inhibit synthesis of beta 1-3 glucan by targeting beta 1-3 glucan synthase in the target enzyme leads to leakage of membrane and cell death
- Basis for selective inhibition of fungi: mammalian cells lack this activity
Be able to name the family they belong to, recognize the general structure, discuss the mechanisms of action, the basis for selective inhibition of fungi:
* Rezafungin
- Family: Echinocandin
- LOOK AT STRUCTURE:
- MOA: inhibits the beta 1-3 glucan synthase enzyme, with much longer half-life then the other echinocandin
- Basis for selective inhibition of fungi: Mammalian cells lack this activity
Be able to name the family they belong to, recognize the general structure, discuss the mechanisms of action, the basis for selective inhibition of fungi:
* Flucytosine
- Family: antimetabolie pyrimidine analog
- LOOK AT STRUCTURE:
- MOA: prodrug inhibits thymidylate synthase and interferes with protein synthesis (acts like 5-fu for fungal cells)
- Basis for selective inhibition of fungi: Mammalian cells are unable to convert flucytosine to active metabolite
Human cells do not contain cytosine deaminase and, therefore, do not convert flucytosine to 5-FU. Some intestinal flora, however, do convert the drug to 5-FU, so human toxicity does result from this metabolism.
Be able to discuss the main difference between cell membranes of fungal and human cells. How are these differences exploited in antifungal drugs?
- Ibrexafungerp
- Family: Small molecule inhibitor of glucan synthase enzyme
- LOOK AT STRUCTURE:
- MOA: inhibitor of glucan synthase enzyme
- Basis for selective inhibition of fungi: mammalian cells lack this activity
Be able to discuss the main difference between cell membranes of fungal and human cells. How are these differences exploited in antifungal drugs?
- Tavaborole
- Family: second newest class of antifungal drugs
- LOOK AT STRUCTURE:
- MOA: inhibit LeuRS and thus inhibit protein synthesis
- Basis for selective inhibition of fungi: Boron is essential for activity
Be able to explain the toxicity of amphotericin B. How does this relate to flucytosine therapy?
flucytosine is removed by the kidney…..renal impairment can lead to more toxicity from flucytosine. Amphotericin B causes kidney toxicity. Thus, the two together can be a major issue for the kidney.
Be able to describe why amphotericin B and flucytosine are often used in combination.
- Together they have synergistic effects
- The mechanism of action of amphotericin allows for the cell membrane to be more permeable which allows flucytosine easier access into the fungal cell to cause death
Be able to describe the interaction of azole antifungal agents on cytochrome P450. How does this affect other drug therapies? Why can this be a problem?
-Azoles inhibit CYP450 which can lead to many drug interactions
- They also are metabolized by cyp450
All azoles have a nitrogen 5 member ring that will bind to the iron in CYP450 catalytic site
Be able to recognize the azole functional group and explain its significance for the mechanism of action.
All azoles have a nitrogen 5 member ring that will bind to the iron in CYP450 catalytic site
Be able to explain how the metabolism of flucytosine in fungal cells differs from that in animal cells.
- Flucytosine acts as 5-fu in fungal cells
Be able to explain the reaction that is catalyzed by thymidylate synthase, and how flucytosine inhibits the reaction.
- 5-FdUMP will bind to thymidylate synthase and blocks its ability to convert dUMP to dTMP which essentially leads to starving the cell of base pairs for DNA synthesis and leads to interference with protein synthesis
