WK9 : antifungal CHEMOTHERAPY

What type of organisms are fungi compared to bacteria?

Fungi are eukaryotes (have nucleus, organelles), making them more similar to human cells than bacteria

Why is designing antifungal drugs more challenging than designing antibacterial drugs?

Because fungi are eukaryotic like humans, so finding selective targets is harder without harming host cell

What are three common superficial fungal infections?

thrush (oral), athlete's foot, dandruff.

What antifungal ingredient in shampoo helps treat dandruff?

Ketoconazole — kills Malassezia fungi on t

What key sterol is found in fungal cell membranes but not in human membranes?

Ergosterol (humans use cholesterol).

What cell wall component do fungi have that humans lack?

Chitin, glucans, and mannans

What fungal-specific enzyme can activate certain prodrugs?

Cytosine deaminase

What are the three main targets for antifungal drugs?

Cell membrane (ergosterol), cell wall (chitin/glucans), and DNA/RNA synthesis

Why is the fungal cell wall a good drug target?

humans have no cell wall, so drugs targeting it are selectively toxic.

What are the two main classes of membrane-active antifungals?

Azoles and Polyenes

What is the key difference in their mechanisms?

Azoles inhibit ergosterol synthesis; Polyenes bind directly to ergosterol and disrupt membrane integrity.

Which enzyme in ergosterol biosynthesis do azoles inhibit?

14α-demethylase (lanosterol 14α-demethylase

What happens if ergosterol synthesis is blocked?

Fungal membranes become weak, leaky, and dysfunctional

What was the first major human-use azole antifungal?

Clotrimazole (1969, topical use)

What key advance did ketoconazole introduce?

First oral systemic azole antifungal.

What year was fluconazole introduced and why was it a breakthrough

1988; better solubility, safety, and oral bioavailability.

What part of the fungal enzyme do azoles bind to?

The heme iron in the active site of cytochrome P450 14α-demethylase.

How does this binding inhibit the enzyme?

It blocks substrate (lanosterol) access, preventing demethylation

what is the main example of a 2nd generation azole?

Ketoconazole.

What was the main limitation of early imidazoles?

Poor metabolic stability (<5% excreted unchanged).

What structural change distinguishes triazoles from imidazoles?

Triazoles have a 3-nitrogen ring vs. imidazoles' 2-nitrogen ring.

What is a key example of a triazole antifungal?

Fluconazole

What advantage do triazoles have over imidazoles?

Better metabolic stability, solubility, and safety profile

Why was UK-47265 not widely adopted despite good activity?

High liver toxicity and teratogenic risk.

What modification in fluconazole improved its systemic use?

replacement of chlorine with fluorine atoms — better solubility and stability

What is the classic example of a polyene antifungal?

Amphotericin B.

How do polyenes kill fungal cells?

Bind ergosterol, form membrane pores → leak ions → cell death.

What is the major clinical drawback of amphotericin B?

Significant nephrotoxicity (kidney damage).

What is griseofulvin's mechanism of action?

Binds fungal microtubules → disrupts mitosis.

What type of infections is griseofulvin mainly used for?

Superficial skin and nail infections (ringworm, athlete's foot).

What is the main antifungal that targets DNA/RNA synthesis?

Flucytosine (5-FC).

What does 5-fluorouracil (activated flucytosine) inhibit

thymidylate synthase (DNA synthesis) and incorporates into RNA → disrupts protein synthesis

Why is flucytosine selectively toxic to fungi?

Human cells lack cytosine deaminase, so they can't activate it to its toxic form.

What are two mechanisms of flucytosine resistance?

1. Decreased uptake (permease mutation)

2. loss of activating enzymes (cytosine deaminase/UMP pyrophosphorylase)

Why is flucytosine rarely used as monotherapy?

Rapid resistance development.

For which infections is flucytosine still used today?

Cryptococcal meningitis and severe candidiasis.

How is flucytosine usually administered?

in combination with amphotericin B or fluconazole

What is the molecular target of echinocandins?

β-(1,3)-D-glucan synthase.

Name a clinically used echinocandin.

Caspofungin acetate (Cancidas).

Why are echinocandins highly selective antifungals?

Humans lack cell walls and the enzyme targeted.

What are the key structural components of the fungal cell wall?

Chitin, β-glucans, and mannoproteins

What happens when β-glucan synthesis is inhibited?

The cell wall weakens, leading to osmotic lysis

How are echinocandins administered and why?

Intravenously — poor oral bioavailability due to peptide structure.