Duncan Antifungals

Question 1

Polyene Drugs

Answer 1

Amphotericin B

Question 2

Amphotericin B Structural Features

Answer 2

Structure similar to membrane phospholipid w/ 7 conjugated double bonds

1. Hydrophilic “rod”
2. Hydrophobic “rod”
3. Polar, negative charged portion (COOH)
4. Polar, positive charged sugar

Question 3

Amphotericin B Formulations

Answer 3

Deoxycholate
Lipid Formulations - Abelcet, Ambisome

Question 4

Amphotericin B Lipid Formulations

Answer 4

Decreases nephrotoxicity and allows for higher dosing
Abelcet = ring-like structure
Ambisome = lipsome formulation

Question 5

Amphotericin B MOA

Answer 5

Membrane targeting agent (like associates with like) - similar MOA to polymyxin

Initially interacts with LPS, is recruited to fungal membrane, and then is able to interact with lipid bilayer

Hydrophilic, ionic head associates with hydrophilic heads of phopholipids

Hydrophobic rod can insert into nonpolar interior of membrane

Unfavorable insertion of hydrophilic rod into nonpolar interior

Question 6

What interaction provides major binding energy for Amphotericin B?

Answer 6

Binding interaction between ergosterol and hydrophobic rod of Amphotericin B

Question 7

Details of MOA of Amphotericin B

Answer 7

Forms pores in membrane

However, modified Amphotericin B that cannot form pores in the membrane still has full antifungal activity

Question 8

What part of the Amphotericin B molecule plays an important role in stabilizing the pore?

Answer 8

C35 OH

Removing C35 OH abolishes pore formation and only slightly reduces activity

Question 9

Removing _____ abolishes activity of Amphotericin B

Answer 9

mycosamine (AmdeB)

Question 10

Structural modifications made to Amphotericin B molecule to reduce nephrotoxicity

Answer 10

Adding urea-based side chains reduce nephrotoxicity and maintain antifungal activity

Question 11

Why doesn’t Amphotericin B affect bacteria?

Answer 11

Bacterial membranes don’t contain sterols, such as ergosterol

Question 12

Ways to minimize nephrotoxicity of Amphotericin B

Answer 12

Administer with CCB, such as diltiazem

Salt loading

Question 13

Flucytosine

Answer 13

Prodrug - metabolized into 5-fluorouracil (anti-cancer agent)

Should NOT be used as monotherapy - resistance develops quickly

Frequently used in combination with Amphotericin B for synergy - pore formation from Amphotericin B enhances penetration of flucytosine

Question 14

Flucytosine MOA

Answer 14

Metabolic antagonist - inhibition of DNA and RNA synthesis

Question 15

Enzyme that converts flucytosine → 5-FU

Answer 15

Cytosine deaminase (high activity in fungi, low activity in humans)

Question 16

Imidazole Structure

Answer 16

2 nitrogens in 5 atom ring

More toxic than triazoles

Mostly used topically due to systemic toxicities

Question 17

Imidazole Drugs

Answer 17

Miconazole

Clotrimazole

Econazole

Ketoconazole (newer, less toxic imidazole)

Question 18

Triazole Structure

Answer 18

3 nitrogens in 5 aton ring

Less toxic than imidazoles

Can be used systemically

Question 19

Triazole Drugs

Answer 19

Fluconazole

Itraconazole

Voriconazole

Posaconazole

Isavuconazole

Question 20

Isavuconazole

Answer 20

Significantly higher aqueous solubility than other triazoles because of prodrug (isavuconium) form side chain (aminocarboxyl portion) - isavuconium side chain is rapidly removed in plasma by plasma esterases

Cyclodextrin-free solution

Question 21

Azoles MOA

Answer 21

Metabolic antagonists

Block biosynthesis of ergosterol

Primarily fungistatic

Question 22

Imidazole MOA

Answer 22

Directly interacts with cell membrane → contributes to its toxicity

Question 23

Triazole MOA

Answer 23

Inhibit lanosterol demethylase (CYP450) → instead of making ergosterol, pathway makes 14alpha-methyl ergosterol, which packs more loosely in membranes → leaky and unstable membranes

Question 24

Azoles DDIs

Answer 24

CYP3A4 - Ketoconazole and Itraconazole

CYP2C9 (Warfarin) - Fluconazole

Systemic imidazoles interact with H2RAs, PPIs, and. antacids

Question 25

Efinaconazole

Answer 25

First approved azole for **topical** treatment of onychomycosis Has improved activity due to **reduced keratin binding** (nail-binding), which allows greater penetration to sites of fungi

Question 26

Allylamines Drugs

Answer 26

Terbinafine (PO) Naftiline (topical)

Question 27

Allylamine and Thiocarbamate MOA

Answer 27

Block **epoxidase** step in ergosterol synthesis

Question 28

Griseofulvin MOA

Answer 28

Affects microtubules → affects cell division Can bind to keratin in skin and nails

Question 29

Pentamidine Structure

Answer 29

Central sting of 5 CH2s sandwiched between two para-modified phenols Each phenol has identical amino side chain

Question 30

Pentamidine MOA/Use

Answer 30

Alters nucleic acid function Used for PCP pneumonia as an alternative to Bactrim

Question 31

Polyoxins and Nikkomycins Structure

Answer 31

Pyrimidine linked to a peptide Structural analogue of UDP-N-Acetyl-Glucosamine

Question 32

Polyoxins and Nikkomycins MOA

Answer 32

Target cell wall biosynthesis by blocking biosynthesis of chitin

Question 33

Papulacandins and Echinocandins/Pneumocandins MOA

Answer 33

Noncompetitive inhibitor of glucan synthase Work synergistically with Amphotericin B, polyoxins, and nikkomycins Fungicidal

Question 34

Echinocandin/Pneumocandin Structure

Answer 34

Lipopeptide Cyclic hexapeptide nucleus

Question 35

Glucan Synthase

Answer 35

Enzyme made up of multiple subunits: FKS1, FKS2, and Rho1

Question 36

What do echinocandins/pneumocandins bind to?

Answer 36

FKS1

Question 37

Echinocandin/Pneumocandin Sensitivity and Resistance

Answer 37

Fungi are uniquely sensitive due to the unique use of glucan ploysaccharide in cell wall Fungi with little to no glucan in cell wall are resistant Mutations in FKS1 gene cause resistance

Question 38

Limitations of Echinocandins/Pneumocandins

Answer 38

Limited oral absorption - IV only Increasing resistance

Question 39

Ibrexafungerp

Answer 39

Newest glucan synthase inhibitor - FDA approved in June 2021 for candidiasis

Question 40

Ibrexafungerp Structure

Answer 40

Triterpenoid core

Question 41

Ibrexafungerp Advantages

Answer 41

Oral bioavailability Activity/stability in serum environment

Question 42

Ibrexafungerp MOA

Answer 42

Binds to and inhibits FKS1p at a similar site to echinocandins/pneumocandins → fungal cell wall loses structural integrity → fragile cell wall subject to lysis (osmotic pressure) Sufficiently different from echinocandins/pneumocandins to not be affects by mutations leading to echinocandin/pneumocandin resistance