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BIOL3027 - Selective Toxicity > VJ - Antifungals > Flashcards

VJ - Antifungals Flashcards

1
Q

What are Fungi? (4)

A
  • Eukaryotes (unicellular and multicellular, cell nucleus, etc.)
  • Heterotrophs except with lichen (algae/cyanobacteria)
  • Mostly opportunistic (secondary) infection
  • Cause superficial, (sub)cutaneous and systemic (tissues/organs) = mycoses
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2
Q

What are the 3 problematic classes of fungi for humans?

A
  • Dermatophytes
  • Yeast
  • Moulds
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3
Q

What are characteristics of Dermatophytes? (2)

A
  • Commensals that metabolize keratin
  • Cause common superficial diseases (e.g., ringworm, athlete’s foot, jock itch)
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4
Q

What are characteristics of Yeast? (4)

A
  • Unicellular, reproduces by fission or budding
  • Often commensal (pharynx, GI tract, vagina)
  • Diseases: e.g., Candida (C. auris, C. albicans) and Cryptococcus (C. neoformans)
  • Causes mucosal infections (e.g., thrush) and systemic infections (e.g., meningitis)
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5
Q

What are characteristics of Moulds? (3)

A
  • Multicellular, form colonies, reproduce through sporulation
  • Commonly found in soil and organic matter
  • Diseases: e.g., Aspergillosis (from Aspergillus sp.) - often begins in airways, can spread systemically
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6
Q

How are fungi becoming a growing problem? (3)

A
  • Usually in immunocompromised (AIDS, immunosuppression, radiotherapy, organ transplants, etc.)
  • Hospital acquired infections: pregnancy, diabetes, antibiotic treatment
  • Becoming increasingly resistant to antifungals
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7
Q

What makes fungi different to other eukaryotes?

A

Cell wall containing glucans and chitin, as well as a cell membrane containing ergosterol

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8
Q

Why are fungal infections challenging to treat? (3)

A
  • Fungi grow slowly and infect poorly penetrated tissues
  • Require prolonged treatment due to resistance
  • Have a unique cell wall with glucans, chitin, and a membrane with ergosterol
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9
Q

What is the difference between fungistatic and fungicidal antifungals?

A

Fungistatic: Inhibits fungal growth

Fungicidal: Kills fungal cells

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10
Q

What are major sites of action for antifungal drugs? (5)

A

1) Inhibition of nucleic acid synthesis

  • Flucytosine

2) Inhibition of proteins synthesis
Sordarins

  • AzasordarinsStructure and synthesis of fungal cell walls

3) Disruption of microtubules and inhibition of mitosis

  • Griseofulvin

4) Disruption of cell wall

  • Inhibitors of glucan synthesis (Echinocandins)
  • Inhibitors of chitin synthesis (Nikkomycin)

5) Disruption of cell membrane

  • Inhibitors of ergosterol synthesis (Azoles/Allylamines)
  • Direct membrane damage (Polyenes)
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11
Q

Describe the fungal cell wall structure (2)

A

Inner layer: β‐1,3‐glucan, β‐1,6‐glucan, chitin

Outer layer: mannose-proteins (involved in cell adhesion, immune evasion)

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12
Q

What are the functions of the fungal cell wall? (4)

A
  • Offers environmental protection against osmotic forces
  • Involved in morphogenesis (cell division, budding, filamentous growth)
  • Prevents leakage of mannose-proteins by providing an anchoring point
  • Mannose-proteins aid in cell adhesion, structure, and immune evasion (e.g., dectin-1 in Candida albicans)
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13
Q

hat is the role of Uracil diphosphate (UDP) in fungal cell wall synthesis?

A

UDP is a carrier molecule for glucose and N-acetyl glucosamine

It activates the following synthases:
* Chitin synthase
* β-1,3-glucan synthase (FKS1p and FKS2p)
* β-1,6-glucan synthase

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14
Q

What are Echinocandins and their role in antifungal treatment? (5)

A

Echinocandins are β-1,3-glucan synthesis inhibitors (natural and semi-synthetic)

  • Cyclic hexapeptides that inhibit β-1,3-glucan synthase (FKS1p subunit) via non-competitive inhibition (binding site unresolved)
  • Known as the “penicillin of antifungals,” they are fungistatic and fungicidal
  • Effective against Candida and Aspergillus infections
  • Good distribution in tissues, including the brain; however, they have poor bioavailability, requiring intravenous administration
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15
Q

What is Nikkomycin Z and its role in antifungal treatment? (3)

A

Nikkomycin Z is a chitin synthesis inhibitor that competitively inhibits chitin synthase

  • It is believed to enter cells via a peptide endocytosis mechanism
  • Currently used in veterinary settings but has not advanced beyond Phase I clinical trials in humans due to high costs
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16
Q

What is the role of ergosterol in fungal cell membranes? (3)

A
  • Ergosterol serves a similar function to cholesterol in other eukaryotes
  • It is thought to be related to climatic instabilities (varying humidity and moisture) in fungi’s ecological niches (plant and animal surfaces, soil)
  • Ergosterol impacts membrane fluidity and functionality
17
Q

How do polyenes cause direct membrane damage in fungi? (4)

A
  • Polyenes may act as ionophores, binding to ergosterol (more than cholesterol) to form pores
  • This increases membrane permeability, particularly to monovalent cations (e.g., K+)
  • The result is leakage, cell lysis, and cell death (fungicidal effect)
  • Other hypotheses include reactive oxygen species (ROS) generation and functioning as extramembranous sponges that “steal” ergosterol
18
Q

What is Amphotericin B and how does it function as an antifungal? (3)

A
  • Amphotericin B (AMB) is a polyene antimicrobial agent that is poorly water-soluble, often used as lipid complexes
  • It selectively targets ergosterol in fungal cell membranes, as it binds better to ergosterol than cholesterol
  • While it has low affinity for cholesterol, this reduces but does not eliminate its toxicity to human cells
19
Q

How is ergosterol targeted by antifungal drugs? (3)

A
  • Squalene epoxidase: Inhibited by allylamines and thiocarbamates
  • Lanosterol α14 demethylase: Inhibited by azoles (major antifungal class)
  • Δ14 sterol reductase and Δ8 sterol isomerase: Targeted by morpholines (fungi-specific enzymes)

Reducing ergosterol levels and increasing levels of intermediates = toxicity

20
Q

How do allylamines inhibit ergosterol synthesis in fungi? (3)

A
  • Allylamines non-competitively inhibit squalene epoxidase, reducing ergosterol levels and increasing toxic squalene levels (fungicidal effect)
  • Effective against nail and skin dermatophytes, though they have a narrow spectrum and significant side effects when taken orally
  • Mammalian cells share this enzyme in cholesterol synthesis
21
Q

How do azoles and triazoles inhibit ergosterol synthesis in fungi? (3)

A

Azoles and triazoles are the largest class of antifungals, with broad-spectrum activity and can be taken orally or intravenously

  • They competitively inhibit lanosterol α14 demethylase, blocking ergosterol synthesis
  • Mammalian cells also have this enzyme, but azoles have much lower affinity (IC50 of 1 nM in Candida vs. 1 μM in human cells), making them less toxic to humans
22
Q

What are the structural requirements for azole antifungals and how do they interact with other drugs? (3)

A
  • Azoles require a basic imidazole or 1,2,4-triazole ring to bind the iron atom in the heme group of the enzyme’s active site
  • The remaining structure binds to the apoprotein, with a large nonpolar part that mimics a steroid molecule
  • Azoles inhibit cytochrome P450 (CYP 3A4), potentially interacting with other drugs metabolized by this enzyme (e.g., cyclosporine)
23
Q

How do morpholines inhibit ergosterol synthesis in fungi? (2)

A
  • Morpholines inhibit both Δ14 reductase (IC50: 2.93 µM) and Δ8 isomerase (IC50: 1.8 nM), creating a synergistic effect by blocking two steps in the same pathway
  • Commonly marketed as Curanail, Loceryl, Locetar, or Odenil, they are available over-the-counter as nail lacquers
24
Q

How does Flucytosine function as an antifungal agent? (3)

A

Flucytosine is used as an adjunctive treatment for systemic fungal infections (e.g., Cryptococcal meningitis) due to high resistance rates and its fungistatic nature

It is converted to 5-fluorouracil (5-FU) by cytosine deaminase

  • 5-FU inhibits thymidylate synthase and can be incorporated into RNA, disrupting RNA function and protein synthesis
25
Q

What is Griseofulvin, and how does it work as an antifungal?

A

Griseofulvin, the first antifungal (from Penicillium), interacts with tubulin to disrupt microtubule and spindle formation, arresting cells in metaphase (fungistatic effect)

  • It binds to keratin and selectively targets fungal cells through energy-dependent uptake (100x more than in mammalian cells)
  • Administered orally for dermatophyte infections (ineffective topically)

BIOL3027 - Selective Toxicity (17 decks)

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