Intro to Veterinary Mycology and Antifungal Drugs

Question 1

describe the gross appearance of the mold and yeast forms of fungi

Answer 1

the mold form is the hyphae (multicelllar); yeast are single cellular units

Question 1

explain how fungi differ from bacteria

Answer 1

fungi are eukaryotic, have membrane bound organelles, have a fastest cell division of 18 hours (much slower than prokaryotes), their ribosomes are 80S (versus prok 70S), none are obligate anaerobes, they are not motile, they have their own sterol in the plasma membrane (ergosterol) (proks don’t have sterols except mycoplasma that has cholesterol), and their cell wall is composed of glucans (alpha and beta), chitin, mannans, and melanin (compared to prok peptidoglycan, LPS, lipotechoic acid, and lipoproteins)

Question 2

define yeast versus hyphae

Answer 2

yeast: unicellular fungi; reproduce by budding

hyphae: multicellular fungi; reproduce asexually by forming conidia (spore) at tip of hyphae following a period of rapid growth; this is the mold form

Question 3

define mycelium

Answer 3

hyphae grow in thick masses form a mycelium

Question 4

define saprophyte

Answer 4

organisms that acquire nutrients from dead or decaying organic matter

Question 5

define dimorphic

Answer 5

dimorphic fungi can exist as either mold (in cold environments; outside body), or as yeast (in heated environments, like the body of animals)

Question 6

define conidia

Answer 6

the spore at the tip of a hyphae asexually reproducing

Question 7

define conidiophore

Answer 7

hyphae bearing a conidia (spore)

Question 8

describe the composition and structure of the fungal cell wall (3)

Answer 8

multi-layered and more complex than most bacteria!!

1. plasma membrane contains ergosterol
2. glycoproteins (mannoproteins) compose up to 20% of cell wall
3. complex polysaccharides compose 80% of cell wall:
   3a. glucans (alhpa or beta): form triple helix that crosslink and provide strength
   3b. chitin: provides rigidity
   3c. melanin: pigment that resists oxidant stress from host

Question 9

what are the 8 classes of antifungal drugs?

Answer 9

1. polyenes: amphotericin B
2. allylamine
3. azoles
4. echniocandins
5. nikkomycin
6. griseofulvin
7. 5-fluorocytosine (flucytosine): not used in vet med but targets DNA/RNA synth in fungal cells
8. iodide

Question 10

describe the mechanism of action of polyenes and give an example and describe that example

Answer 10

polyenes bind to sterols (esp ergosterol) in the fungal plasma membrane and form a pore that causes an increase in permeability, causing fungi to swell and die from osmotic lysis

an example is amphotericin B: which was the gold standard for treating most fungal diseases in companion animals, administered IV (polyenes have poor GI absorption) but has high toxicity!! because it binds to proximal tubule epithelial cells in the kidney and can lead to loss of renal function; can prepare with liposomes to be less toxic, but these lipid formulations are more expensive

Question 11

give the mechanism of action of allylamines, drug forms, toxicity, and resolution

Answer 11

1. interfere with an early step in ergosterol synthesis by inhibiting the enzyme squalene epoxidase
2. comes in oral or cream form mainly used to treat dermatophyte infections of skin (ringworm) and nails
3. minimal toxicity
4. resolution usually takes weeks to months

Question 12

give the mechanism of action, drug forms, toxicity, and resolution of azoles

Answer 12

1. interfere with ergosterol synthesis by inhibiting the enzyme required to convert lanosterol to ergosterol; accumulation of lanosterol induces a gene that converts lanosterol to a toxic sterol to kill the fungus
2. it takes weeks for the toxic sterols to accumulate to kill a fungus so therapy is long term and should be administered for 1 month after clinical disease is no longer detectable
3. has oral and topical formulations so is easy to administer
4. causes no nephrotoxicity so is frequently used by clinicians

Question 13

give the mechanism of action, drug forms, and toxicity of echinocandins

Answer 13

1. block beta (1,3)D-glucan synthase, which is essential for B(1,3)D-glucan (80% of cell wall) synthesis by inhibiting the hyphal tip and branch point growth, and is also active against some yeast, leading to osmotic lysis
2. minimal toxicity
3. must be given IV (poor GI absorption)

Question 14

give the mechanism of action, drug forms, toxicity, and efficacy/synergy of nikkomycin Z

Answer 14

1. blocks synthesis of chitin via competitive analogs of a substrate of chitin synthase enzyme, causing treated fungi to swell and rupture by osmotic lysis
2. low toxicity
3. oral formulation
4. effective against many dimorphic pathogenic fungi and may work synergistically with other antifungal drugs (azole, polyene, or echniocandin)

Question 15

give the mechanism of action, drug forms, toxicity, and resolution of griseofulvin

Answer 15

1. blocks mitosis of fungal cells by binding to tubulin (a protein found in microtubules)
2. used orally for dematophyte (skin and nail) infections; give with a fatty meal (like peanut butter) to increase absorption
3. concentrates in keratinized epithelium; takes weeks to reach therapeutic levels and proper distribution

Question 16

describe iodides

Answer 16

1. MOA unknown
2. most cost effective antifungal
3. give orally or IV
4. effective for some, but not all fungal infections, and also for chronic bacterial infections (lumpy jaw or wooden tongue in cattle)