Dr. Brown Antifungals

Question 1

How are Fungal infections classified?

Answer 1

Superficial or systemic

Question 2

Fungals are similar to human cells, what is one difference?

Answer 2

Ergosterol in the cell wall (drug target - Ergosterol biosynthesis)
Humans have Cholesterol in the cell wall

Question 3

Which type of Antifungals inhibit fungi by interacting with Ergosterol Biosynthesis?

Answer 3

Azole Antifungal (5-membered N-containing-ring)
can also contain other Heteroatoms (O, S)

Question 4

Where does the Azole-ring in Antifungal drugs bind?

Answer 4

CYP450-heme protein of the fungi (involved in Ergosterol synthesis)

Example: Fluconazole (2x 1,2,4 triazole)

Question 5

What are the most common types of Antifungal groups available?

Answer 5

-Imidazole (2 N)
-1,2,3 triazole (3 N)
-12,4 triazole (3 N)

Question 6

What might Azole Antifungals Cross-react with?

Answer 6

-Human CYP Isozyme (3A4, 2C19, 2D6, 2C9,..)

-not a big deal for topical infection, but for SYSTEMIC infections

Question 7

What are Allylamine drugs?

Answer 7

-contain an Allyl group: CH2 - CH = CH -
-they inhibit squalene epoxidase (enzyme) responsible for ergosterol production
-the cell cant add appropriate steroids to the cell membrane

Question 8

The consequence of Allylamine acting on fungi?

Answer 8

-The fungal cell can not add appropriate steroids to the cell membrane
-Build up of squalenes

Question 9

Examples of Allylamines

Answer 9

-Naftifine
-Terbinafine

Question 10

What drug formulation is suitable based on its chemical structure?

Answer 10

-Highly lipophilic –> Topical and Transdermal

Question 11

What are other squalene inhibitors?

Answer 11

-Butenafine (technically not an Allylamine - but its Phenylring is considered a bioisosteric replacement (same biological function)

-Tolnaftate

both topical and butenafine with a wider spectrum of activity

Question 12

What structural feature do all Squalene inhibitors share?

Answer 12

Naphthalene ring in the structure
-not necessarily part of the pharmacophore
-provides lipophilic character

Question 13

What are Polyenes?

Answer 13

-Poly-many-alkenes
-contain many alkenes (double-bonds)
-interact directly with fungal cell membrane
-insert themselves into the fungal cell membrane and create a pore in the membrane -> ions and water get through

Question 14

Example of a Polyene?

Answer 14

Amphotericin B

Question 15

MOA of Amphotericin B

Answer 15

-The polyene side interacts with Ergosterol (both are lipophilic)

-The polyol (polyalcohol) side will face the inner side of the pore -> water-soluble side for water and ion interaction

-the sterol A-binding site acts as an anchor - stabilizing the drug in the cell membrane of the fungi

Question 16

What is a factor for systemic safety in polyene drugs?

Answer 16

Number of consecutive conjugated double bonds
The more the safer

Question 17

What is Flucytosine?

Answer 17

-Pyrimidine anti-metabolite (false nucleotide - looks like a nucleotide but it does not work)

Question 18

MOA of Flucytosine

Answer 18

-Flucytosine = 5-FC
5-FC is converted to the active drug 5-FU by the Cytosine deaminase -> 5-FU (5-Fluorouracil) inhibits DNA-synthesis in the fungal cell

Question 19

Why is this drug not harmful to humans?

Answer 19

Because humans do not have the Cytosine deaminase enzyme converting 5-FC to 5-FU

Question 20

How is Flucytosine administered?

Answer 20

-Synergistically with amphotericin B
-using the pores created by amphotericin B to get into the cell

Question 21

What are Echinocandins?

Answer 21

-Lipopeptides with peptide bonds in the cyclic structures
-has a lipophilic tail
-Example: Micafungin

Question 22

MOA of Echinocandins

Answer 22

-Interfere with Cellwall Biosynthesis

-Inhibitor of the beta (1,3) glucan synthase enzyme

Question 23

What are Antifungal resistance mechanisms?

Answer 23

-For Azoles: Efflux pumps
-Polyenes: change in membrane composition, polyenes need Ergosterol to anchor into the cell membrane

-Azoles, Allylamines: Overexpression of drug targets leads to decreased efficacy of the drug
Azole - CYP450
Allylamines - squalene epoxidase

-5-FC: the fungal cell reduces cytosine deaminase activity