Antifungal drugs

Question 1

Mycoses

Answer 1

Fungal diseases

Question 2

Superficial mycoses affect:

Answer 2

scalp
nails and skin
mucous membranes (oral cavity and vagina)
not life-threatening

Question 3

Systemic mycoses

Answer 3

affect internal organs (kidneys, lung, brain)

fatal in severely immunocompromised patients

Question 4

Fungal pathogens

Answer 4

are eukaryotes – implications for drug targets and therapy

belong to the category of “opportunistic pathogens”

Question 5

What puts patients at higher risk of developing fungal infections

Answer 5

1. Impaired immune system  
  HIV/AIDS 
  organ transplantation
  a course of long-term broad-spectrum antibiotics treatment
  premature birth
  cancer 
  hospitalisation in ICU

2. Menstrual cycle in women: ~70% experience at least one episode of vaginitis caused by C. albicans (at, or around the time of ovulation)

Question 6

Fungal diseases

Answer 6

Difficult to treat
Impossible to eradicate (caused by commensal, environmental species)
High cost to the health-care systems
Their frequency has increased in recent years
Immunosuppresed individuals account for an increasing % of the human population

Question 7

The fungal cell wall

Answer 7

Crucial for survival of the cell
Has complex structure and composition
Has no equivalent organelle in human cells
An ideal target for antifungals
it has: Skeletal components and Matrix components

Question 8

Skeletal Cell Wall components

Answer 8

Glucan
Constitutes ~55-60% of the CW
Two types of polymers of D-glucose:
beta 1,6 Glucan – (Glucose residues linked by beta-1,6 bonds)
beta 1,3 Glucan – (Glucose residues linked by beta-1,3 bonds)

Chitin
~ 2% of the CW
Linear polymer of N-acetylglucosamine

Question 9

Mannan

Answer 9

A complex of ~ glycosylated proteins (mannoproteins)

35-50% of the CW

Question 10

Echinocandins (caspofungin, micafungin)

Answer 10

Inhibit the enzyme beta 1,3 - glucan synthetase
Block synthesis of beta 1,3 glucan
Drugs are fungicidal

Question 11

Are there differences in plasma membranes of human and fungal cells?

Answer 11

PMs (plasma membranes) in fungal cells contain ergosterol, those of human cells contain cholesterol
Ergosterol is an essential component of fungal PMs
In the absence of functional ergosterol biosynthesis fungal cells cannot grow and survive

Question 12

Antifungals that target ergosterol

Answer 12

either bind to resident ergosterol in the plasma membrane

or inhibit different ergosterol biosynthetic enzymes and block de novo biosynthesis of ergosterol

Question 13

Polyene antifungals

Answer 13

Polyenes are fungicidal
Bind to ergosterol, and form pores in the PM
These pores disrupt membrane integrity causing leakage of cell constituents
Have higher affinity for ergosterol than cholesterol
Prolonged application is associated with severe side effects (kidney failure)

Question 14

Amphotericin B

Answer 14

prolonged use has severe side effects. Amp B lipid complex (ABLC) and liposomal Amp B (L-Amp B) formulations reduce the risks
natural in origin

Question 15

Nystatin

Answer 15

used in treatment of oral and GI fungal infections

natural in origin

Question 16

Ergosterol biosynthesis inhibitors (azoles)

Answer 16

Inhibit the enzyme Lanosterol C-14 demethylase
Inhibition of the enzyme:
blocks ergosterol biosynthesis
leads to accumulation of toxic intermediates
causes growth arrest

Question 17

The azoles (imidazoles and triazoles)

Answer 17

are fungistatic
inhibit lanosterol C14-demethylase
Triazoles have higher affinity for the enzyme – hence more potent antifungals

Question 18

RNA & DNA synthesis as targets for antifungals

Answer 18

5-Fluorocytosine

Flucytosine

Question 19

Flucytosine

Answer 19

Taken up by fungal cells
Metabolised by fungal cells to 5-fluorouracil (5-FU)
5-fluorouracil (5-FU) is a toxic antimetabolite
5-FU inhibits fungal DNA and RNA synthesis
Associated with high levels of resistance
Usually used in combination with azoles

Question 20

Resistance to antifungal drugs is caused by

Answer 20

decreased accumulation of the drug (increased efflux or reduced permeability to the drug)
inactivation of the drug
mutations in drug target-encoding genes
Biofilm formation
(growth on plastic surfaces -catheters)
High incidences of intrinsically resistant to azoles (Fluconazole) Candida species (Candida glabrata)

Question 21

The growth polymorphism

Morphological switching from yeast-to-hyphae – the next generation antifungal drug target

Answer 21

It is a strong virulence factor
Depends on tight regulation
Regulators of morphological switching are novel targets for antifungals
Inhibitors of morphological switching are in clinical trials (F2G)

Question 22

Antifungals act on:

Answer 22

cell wall glucan biosynthesis (echinocandins)
ergosterol in the plasma membrane (polyenes)
ergosterol biosynthesis (azoles and allylamines)
Nucleic acids biosynthesis (flucytosine)