7 - Medicinal Chemistry of Antifungal Therapies Flashcards
How many species of fungi are there, and how many are medically important?
80,000 species of fungi; 400 are medically important.
What beneficial roles do fungi play?
Fungi are involved in:
* Breaking down and recycling organic matter
* Production of food and spirits (e.g., cheese, bread, beer)
* Antibiotic production (e.g., penicillin)
* Immunosuppressive drugs (e.g., cyclosporine)
What are the two forms of fungi?
Yeast form (unicellular) and Mold form (multicellular).
What is the leading cause of mortality in immunocompromised patients?
Fungal infections.
What is the common fungal infection in immunocompetent patients?
Candida albicans (Thrush) and skin and nail fungal infections.
Name a true yeast.
Cryptococcus neoformans.
Name a yeast-like fungus.
Candida albicans.
Identify two dimorphic fungi.
Histoplasma capsulatum and Blastomyces dermatitidis.
What class of antifungal drug is Amphotericin B?
Polyene.
What is the mode of action of Amphotericin B?
Amphotericin B binds to ergosterol, generating a pore in the membrane and inducing oxidative burst.
What are the acute toxicities associated with Amphotericin B?
Nausea, vomiting, fever, and hypoxia.
What chronic effect is associated with Amphotericin B?
Nephrotoxicity.
What class of antifungal drug is Fluconazole?
Azole.
What is Fluconazole used for?
Less severe fungal infections and prophylactically in immunocompromised patients.
How does Fluconazole exert its effects?
Fluconazole targets the heme protein and co-catalysed cytochrome P450 dependent demethylation of lanosterol
Inhibition of demethylation enzymes results in depletion of ergosterol
- altering structure and membrane function of fungus
What is a significant side effect of Fluconazole?
MYELOTOXICITY (bone marrow suppression).
- hugely detrimental in already immunosuppressed patients
(White blood cell count does return to normal within 48 hours of discontinuation though)
Other problems include:
Fluconazole is fungistatic
- suppressing rather than curing infection
Emergence of resistance
What is Flucytosine?
A pyrimidine analogue.
How does Flucytosine exert its antifungal effects?
By interfering with DNA and RNA synthesis.
What serious side effect is associated with Flucytosine?
Hepatotoxicity.
What is the first line treatment for C. neoformans?
A 2-week course of Amphotericin B and 5-flucytosine followed by a long-term course of Fluconazole.
What is a major problem with the co-administration of Flucytosine and Amphotericin B?
Increased risk of hepatotoxicity due to nephrotoxicity.
What is the significance of Benzimidazoles in antifungal therapy?
They represent proof of concept for new treatments with reduced toxicity and improved efficacy.
What process do microtubules undergo that is affected by Benzimidazoles?
Treadmilling (polymerisation and depolymerisation).
How does Mebendazole, a derivative of Benzimidazole, affect cellular mitosis?
By blocking the dimerisation interaction between α and β-tubulin, inhibiting microtubule polymerisation.
Fluconazole is primarily fungistatic, meaning it _______.
suppresses rather than cures the infection.
What causes the side effects of Amphotericin-B?
These side effects are due to human ergosterol and fungal ergosterol being structurally analogous enough that amphotericin B also binds to human membranes and this causes toxic effects, especially in the case of nephrotoxicity, predominately due to changes distal tubule permeability, which causes wasting of Na+, K+, and Mg2+, this results in reduced glomerular filtration
What are the side effects associated with Fluconazole?
Toxicity - myelotoxicity - bone marrow suppression, meaning that leukocytes, which are cells that are involved in the body’s immune response, aren’t synthesised.
* Hugely detrimental in patients with already suppressed immune systems, allowing for further infections.
* Importantly, white blood cell counts do begin to return to normal within 48 hours of discontinuation of treatment.
* Emergence of resistance.
How is resistance to Flucytosine acquired?
What is the MOA of benzimidazole?
What is the MOA of Benzimidazole derivative Mebendazole?
How are Benzimidazoles metabolised?
