Lesson 8.3. Antifungal

cell wall

Common targets of Antifungals:

a. _______________ composed of chitin and glucans

b. __________________ cell membrane

a = ?

ergosterol

Common targets of Antifungals:

a. _______________ composed of chitin and glucans

b. __________________ cell membrane

b = ?

Polyenes

ANTIFUNGAL:

• macrocyclic lactones with amphoteric property.

• used for mycoses (Histoplasma, Blastomyces, Coccidioides) molds (Aspergillus), yeast (Candida), filamentous (Fusarium)

ergosterol

MOA OF POLYENES:

a. binds ___________ to form pores in the membrane

b. leads to _________________________

a = ?

cellular leakage and death

MOA OF POLYENES:

a. binds ___________ to form pores in the membrane

b. leads to _________________________

b = ?

Nystatin

POLYENES:

• topical agent

Nystatin Structure

POLYENES

Amphotericin B

POLYENES:

• IV agent

Amphotericin B Structure

POLYENES:

Azole

potent CYP 450 Inhibitor

triazole

Azoles can be:

a. _____________ (systemic)

b. _____________ (topical except ketoconazole)

a = ?

imidazole

Azoles can be:

a. _____________ (systemic)

b. _____________ (topical except ketoconazole)

b = ?

ergosterol synthesis

MOA OF AZOLES:

a. inhibits ________________________

b. blocks ______________________ of lanosterol

a = ?

oxidative demethylation

MOA OF AZOLES:

a. inhibits ________________________

b. blocks ______________________ of lanosterol

b = ?

Ketoconazole

AZOLES:

• both topical and systemic imidazole

Ketoconazole Structure

Itraconazole

AZOLES:

• requires low pH for gastric absorption like ketoconazole

Itraconazole Structure

AZOLE:

Fluconazole

AZOLE:

• uniquely contain 2 triazole rings

Fluconazole Structure

AZOLES:

Allylamines

used topically for dermatophytic infection (Tinea) and systemically for onychomycosis caused by Trichophyton, Microsporum

squalene epoxidation

MOA of Allylamines

• inhibits ergosterol synthesis by blocking ____________________________

Terbinafine

ALLYLAMINES:

• used as a topical/systemic agent

Naftifine and Butenafine

ALLYLAMINES:

• used as a topical agent only

Terbinafine Structure

ALLYLAMINES

Naftifine Structure

ALLYLAMINES

Butenafine Structure

ALLYLAMINE:

Echinocandins

cyclic peptides with large lipophilic groups

Deep Invasive Candidiasis

Use of Echinocandins

cell wall

MOA of Echinocandins:

a. inhibits fungal ___________ synthesis

b. blocks _______________________ resulting to decreased cell wall rigidity

a = ?

1,3-β-D-glucan synthesis

MOA of Echinocandins:

a. inhibits fungal ___________ synthesis

b. blocks _______________________ resulting to decreased cell wall rigidity

b = ?

Caspofungin Structure

ECHINOCANDINS

Anidulafungin Structure

ECHINOCANDINS

Micafungin Structure

ECHINOCANDINS

Flucytosine

• prodrug deaminated into 5-Fluorouracil (5-FU)

• blocks DNA synthesis by blocking thymidylate synthase. Used for cryptococcus meningitis in AIDS patients.

Griseofulvin

• disrupts mitotic spindle by binding to microtubule protein to block mitosis

• used for Microsporum, Epidermophyton and Trichophyton infection

Ciclopirox

• MOA is unclear but hypothesized to produce ROS

• used for Candida, Epidermophyton and Trichophyton

Tolnaftate

topical agent for tine infection and works by inhibiting epoxidation of squalene (similar to allylamine)

Undecylenic Acid

• fungistatic agent

• MOA is unclear but hypothesize to prevent morphogenesis of fungi from yeast to hyphen form (active infection)

Tavaborole

• inhibits leucyl-tRNA synthetase

• prevents addition of leucine in the growing peptide