Antimicrobial compounds and modes of action - Part 2 (antifungals)

Question 1

What type of microbe is fungi?

Answer 1

Eukaryotic

like human cells are

Question 2

Give 3 examples of fungi

Answer 2

Candida albicans
Histoplasma capsulatum
Aspergillus fumigatus
Cryptococcus neoformans

Question 3

What is another name for antifungals?

Answer 3

Antimycotics

Question 4

What is the general mechanism of action for antifungals?

Answer 4

Weakening of either plasma membrane or cell wall causing cell lysis or inhibition of protein/DNA synthesis

Question 5

What are the 3 main antifungal targets?

Answer 5

Plasma membrane
Cell wall
Protein/DNA synthesis

Question 6

What is the role of ergosterol in fungal membranes?

Answer 6

It is an important sterol found in fungal plasma membranes.
Without ergosterol, the fungal plasma membrane is severely weakened.
Ergosterol and ergosterol biosynthesis is an attractive target for antifungals.

Question 7

Generally describe Azoles antifungals and its mechanism of action (5)

Answer 7

Synthetic antifungals with broad spectrum of activity

Azoles are fungistatic agents

Many different kinds of antifungal azoles

MOA: azoles inhibit lanosterol 14 a-demethylase (ERG11) required to convert lanosterol to ergosterol

1st, 2nd and 3rd generation azoles

Question 8

Outline the 1st generation of azoles

Answer 8

Imidazoles

Characterised by presence of an imidazole ring
Excellent spectrum of activity - but azole ring can be degraded in vivo
e.g. clotrimazole, miconazole

Question 9

Outline the 2nd generation azoles

Answer 9

imidazoles

Increased hydrophilicity
Suitable for oral administration
Still have issues with degradation
e.g. ketoconazole

Question 10

Outline 3rd generation azoles

Answer 10

1,2,4-triazoles
Suitable for oral administration 
Good hydrophilicity 
Triazole ring is less susceptible to degradation in vivo 
e.g. fluconazole, voriconazole

Question 11

Outline the use of polyene antifungals (4) and their mechanism of action

& 2 examples

Answer 11

Macrocyclic (ring containing 12+ membered ring) polyunsaturated compound
Alternate single double carbon-carbon bonds
Amphipathic molecules (hydrophobic and hydrophilic characteristics)
Limited solubility and issues with toxicity (kidney)

MOA: bind to ergosterol, disrupting osmotic integrity of fungal plasma membrane. Causes leakage of intracellular ions and components from the cell. (basically creates space in membrane where material can leak out)

e.g. Nystatin, amphotericin B

Question 12

How can the toxicity of polyene antifungals be reduced?

Answer 12

By altering formation, can package it in a lipid-based delivery system. Reduced interaction with host membranes = reduced nephrotoxicity

Question 13

Outline the echinocandins antifungals, their mechanism of action and example of these

Answer 13

Cyclic glycopeptides
MUST be used intravenously
Very potent against some but not all fungi - e.g. fungicidal to candida, fungistatic to aspergillus

MOA: Inhibits B-glucan synthase required for production of B-1,3 glucans (cell wall)

e.g. caspofungin

Question 14

What is the mechanism of action of Molecular analogue antifungals

Give an example of this

Answer 14

Pyrimidine analogue

MOA: 5-FC inhibits protein and DNA synthesis

5-fluorocytosine

Question 15

Why is it important to consider order of treatment if prescribing a combinational treatment? Outline an example of this

Answer 15

Because you need to appreciate the mechanism of action for each drug -

e.g. tetracycline and penicillin; penicillin requires bacteria to be actively growing in order to work, so if tetracycline is used first there is no growth so penicillin is ineffective

Azoles and polyenes: if azoles are used first, ergosterol depletes so there is no target for amphotericin (polyene).