VJ - Antifungals II Flashcards
What are some mechanisms of antifungal resistance? (2)
- Mutation in glucan synthesis target site
- Fungal cells can send signals to inform neighboring cells
What is the mechanism of resistance to Echinocandins? (2)
- Echinocandins inhibit 1,3-beta-glucan synthase, disrupting cell wall synthesis.
- Mutations in FKS1 reduce drug binding, leading to increased resistance
What are the key stress response mechanisms in fungi under echinocandin exposure? (2)
- HSP90 and Calcineurin aid in stress tolerance.
- RAS and Unfolded Protein Response (UPR) maintain cell wall integrity.
How do fungi exhibit resistance to Polyenes? (2)
- Altered cell membrane permeability due to reduced ergosterol production.
- Some fungi may use alternative sterols to reduce polyene efficacy.
What are 2 response mechanisms to polyene-induced membrane stress?
- Some fungi upregulate ERG5, ERG6, and ERG25 to increase ergosterol synthesis, enhancing tolerance to polyenes.
- HSP90 and Cellular Stress Regulators activate pathways that help fungi survive membrane stress caused by polyenes
What are 3 effects to polyene-induced membrane stress?
Polyene-ergosterol complexes
- disrupt protein gradients
- cause osmotic lysis
- disturb cellular ion balance
What are the resistance mechanisms to Azoles? (4)
1) Reduced Drug Binding
- Mutations in CYP51A/ERG11 reduce azole binding to the target enzyme (e.g., TR₃₄/L98H mutation).
2) Overexpression of Drug Target
- Increased expression of CYP51A raises the target enzyme levels, decreasing drug efficacy.
3) Increased Drug Efflux
- Overexpression of efflux pumps reduces intracellular drug concentration.
4) Hypermutation and Heteroresistance
- MSH2 mutations lead to hypermutation, contributing to genetic diversity and resistance.
- Heteroresistance occurs due to variability in resistance within a fungal population.
How does aneuploidy contribute to antifungal resistance?
Extra copies of chromosomes increase gene dosage, enhancing resistance.
What is involved in the prodrug activation pathway of Flucytosine? (2)
- Flucytosine is a prodrug converted to active metabolites (5-fluorouracil and 5-fluorodeoxyuridine monophosphate) that inhibit DNA/RNA synthesis.
- Mutations in enzymes FCY1, FCA2, and FUR1 block this conversion, preventing the inhibition of DNA/RNA synthesis.
What are two mechanisms of resistance to Flucytosine?
Reduced Drug Uptake:
- Mutations reduce uptake via cytosine permease, lowering intracellular flucytosine levels.
Reduced Affinity for Active Metabolites:
- Point mutations decrease affinity for 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine monophosphate (5-FUMP), diminishing drug action.
How does hypermutation contribute to antifungal resistance?
Hypermutation increases genetic variation, which contributes to the development of resistance.
What are the genetic approaches for identifying new antifungal targets? (2)
- Identify the minimal genome by focusing on essential genes to prevent resistance and non-conserved genes for selective targeting.
- Use knockout screening to determine gene essentiality
What resources are utilized in database comparisons for identifying new antifungal targets? (3)
- Database of Essential Genes (DEG)
- Online Gene Essentiality (OGEE)
- Essential Genes on Genomic Scale (EGGA)
What are some target examples for antifungal therapies? (2)
Inositol Phosphorylceramide Synthase (AUR1)
- Involved in sphingolipid synthesis, a potential antifungal target.
Cryptococcus Trehalose-6-Phosphate Synthase (TPS1) and Trehalose-6-Phosphate Phosphatase (TPS2)
- Regulate glycolysis and are selective targets as they are not found in mammals
