13 Antifungal drugs

Question 1

Fungal diseases are known as mycoses

Answer 1

Superficial mycoses affect:
scalp
nails and skin
mucous membranes (oral cavity and vagina)
not life-threatening
2. Systemic mycoses:
affect internal organs (kidneys, lung, brain)
fatal in severely immunocompromised patients

Question 2

Fungal pathogens

Answer 2

are eukaryotes – implications for drug targets and therapy

belong to the category of “opportunistic pathogens”

Question 3

What puts patients at higher risk of developing fungal infections

Answer 3

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 4

Fungal diseases

Answer 4

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 5

The fungal cell wall

Answer 5

Crucial for survival of the cell
Has complex structure and composition
Has no equivalent organelle in human cells
An ideal target for antifungals

Question 6

The fungal cell wall has

Answer 6

Skeletal components

Matrix components

Question 7

Skeletal CW components

Answer 7

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

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

Question 8

Mannan

Answer 8

A complex of ~ glycosylated proteins (mannoproteins)

35-50% of the CW

Question 9

The fungal cell wall

Answer 9

Has no equivalent in human cells

1,3-Glucan is a key component

Current antifungals that target the CW are inhibitors of 1,3-Glucan biosynthesis

Question 10

Echinocandins (caspofungin, micafungin)

Answer 10

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

Question 11

Are there differences in PMs of human and fungal cells?

Answer 11

PMs 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

Antifungals that bind to resident ergosterol

Answer 13

Polyene antifungals

Question 14

Polyene antifungals

Answer 14

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 15

Polyene antifungals

Answer 15

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

Nystatin used in treatment of oral and GI fungal infections

Both are natural in origin

Question 16

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

Two types of azole antifungals

Answer 17

Imidazoles and triazoles

Question 18

Examples of Imidazoles

Answer 18

Miconazole

Clotrimazole (Canesten)

Question 19

Examples of Triazoles

Answer 19

Fluconazole
voriconazole
itraconazole

Question 20

The azoles (imidazoles and triazoles

Answer 20

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

Question 21

Examples of allylamines

Answer 21

Terbinafine (Lamisil)

Amorolfine (Curanail, Loceryl, Locetar

Question 22

RNA & DNA synthesis as targets for antifungals

Answer 22

5-Fluorocytosine

Flucytosine

Question 23

Flucytosine

Answer 23

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 24

Resistance to antifungal drugs is caused by

Answer 24

decreased accumulation of the drug (increased efflux or reduced permeability to the drug)
inactivation of the drug
mutations in drug target-encoding genes

Question 25

Other factors leading to resistance

Answer 25

Biofilm formation
(growth on plastic surfaces -
catheters)

High incidences of intrinsically resistant to azoles (Fluconazole) Candida species (Candida glabrata)

Question 26

Novel targets for antifungals (in R&D)

Answer 26

are regulators of fungal morphogenesis

Question 27

Fungal pathogens grow in different forms

Answer 27

yeast, pseudohyphae and true hyphae

Question 28

The growth polymorphism

Answer 28

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 29

Antifungals act on:

Answer 29

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

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

Question 30

Antifungal drugs

Answer 30

Have generally lower therapeutic index than antibacterial drugs (fungi more similar to human cells than bacteria)

Most are fungistatic rather than fungicidal

Cause more side effects