Antimycotics

Question 1

What is a fungus?

Answer 1

• eukaryotic organism
• cell wall with glucan and chitin
• heterotroph (more then one nutrient is important)
• ergosterol in cell membrane -> mammals have cholesterol

Question 2

Yeasts

Answer 2

• candida (albicans, glabrata, krusei, parapsilosis, tropicalis)
• cryptococcus (neoformans, gattii) -> pathogen

Question 3

Molds

Answer 3

• diverse
• Aspergillus
• Mucorales

Question 4

Dimorphic fungi

Answer 4

• yeast and/or mold
• endemic
• Histoplasma
• Bastomyces
• Coccidioides
• Sporothrix

Question 5

Name the 4 mycoses (classification)

Answer 5

• superficial mycoses
• subcutaneous mycoses
• cutaneous mycoses
• systemic mycoses

Question 6

What are the risk groups for systemic fungal infections

Answer 6

• stem cells/solid organ transplants
• AIDS patients
• high risk environment
• prolonged antibiotic use
• prolonged neutropenia

Question 7

What are the problems in antimycotic therapy?

Answer 7

• fungi are eukaryotic
• cross resistances observed

Question 8

Name the classes of antifungals

Answer 8

• Pyrimidines
• Echinocandins
• Polyenes
• Azoles

Question 9

Azoles in more detail

Answer 9

• compounds with imidazole or triazole groups
• mode of action: five membered heterocycle binds to heme iron and prevents lanosterol binding to erg11
• contributing to antimycotic effect is toxic sterol (lanosterol is directly combined with erg3 => toxic)
• Fluconazole

Question 10

Polyenes in more detail

Answer 10

• obtained from Streptomyces
• amphiphatic
• mode of action: form extramembranous aggregates that „extract“ ergosterol from plasma membrane
• powerful but toxic (extraction of cholesterol) -> last line defense
• Amphotericin B
• Nystatin

Question 11

Echinocandins in more detail

Answer 11

• cyclic semisynthetic hexapeptide -> cell wall synthesis disruption
• (1,3)-ß-D-glucan is vital for cell wall integrity
• targets Fks1 ((1,3)-ß-D-glucan synthase) as non-competitive inhibitor
• first line therapy against systemic Candida
• Caspofungin

Question 12

Pyrimidines in more detail

Answer 12

• Flucytosine (synthetic fluorinated analogue of cytosine)
• in cytosol flucytosine is rapidly deaminated becoming fluuracil
• 5-fluorouracil causes RNA miscoding
• combination with Amphotericin is gold standard in Cryptococcus therapy

Question 13

Resistance mechanisms

Answer 13

1. overexpression and/or mutations in erg11
2. loss of function mutation in ergosterol synthesis (erg3) -> no toxic sterol
3. mutations in Fks1
4. efflux pumps against azoles -> overexpression of multi-drug-resistance proteins
5. cellular stress response (against azoles) -> overexpression of Hsp90