13 Antifungal drugs Flashcards
Fungal diseases are known as mycoses
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
Fungal pathogens
are eukaryotes – implications for drug targets and therapy
belong to the category of “opportunistic pathogens”
What puts patients at higher risk of developing fungal infections
Impaired immune system
HIV/AIDS organ transplantation a course of long-term broad-spectrum antibiotics treatment premature birth cancer hospitalisation in ICU
- Menstrual cycle in women: ~70% experience at least one episode of vaginitis caused by C. albicans (at, or around the time of ovulation)
Fungal diseases
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
The fungal cell wall
Crucial for survival of the cell
Has complex structure and composition
Has no equivalent organelle in human cells
An ideal target for antifungals
The fungal cell wall has
Skeletal components
Matrix components
Skeletal CW components
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
Mannan
A complex of ~ glycosylated proteins (mannoproteins)
35-50% of the CW
The fungal cell wall
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
Echinocandins (caspofungin, micafungin)
Inhibit the enzyme 1,3 - glucan synthetase
Block synthesis of 1,3 glucan
Drugs are fungicidal
Are there differences in PMs of human and fungal cells?
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
Antifungals that target ergosterol
either bind to resident ergosterol in the plasma membrane
or inhibit different ergosterol biosynthetic enzymes and block de novo biosynthesis of ergosterol
Antifungals that bind to resident ergosterol
Polyene antifungals
Polyene antifungals
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)
Polyene antifungals
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
Azoles
Inhibit the enzyme Lanosterol C-14 demethylase
Inhibition of the enzyme:
blocks ergosterol biosynthesis
leads to accumulation of toxic intermediates
causes growth arrest
Two types of azole antifungals
Imidazoles and triazoles
Examples of Imidazoles
Miconazole
Clotrimazole (Canesten)
Examples of Triazoles
Fluconazole
voriconazole
itraconazole
The azoles (imidazoles and triazoles
are fungistatic
inhibit lanosterol C14-demethylase
Triazoles have higher affinity for the enzyme – hence more potent antifungals
Examples of allylamines
Terbinafine (Lamisil)
Amorolfine (Curanail, Loceryl, Locetar
RNA & DNA synthesis as targets for antifungals
5-Fluorocytosine
Flucytosine
Flucytosine
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
Resistance to antifungal drugs is caused by
decreased accumulation of the drug (increased efflux or reduced permeability to the drug)
inactivation of the drug
mutations in drug target-encoding genes
Other factors leading to resistance
Biofilm formation
(growth on plastic surfaces -
catheters)
High incidences of intrinsically resistant to azoles (Fluconazole) Candida species (Candida glabrata)
Novel targets for antifungals (in R&D)
are regulators of fungal morphogenesis
Fungal pathogens grow in different forms
yeast, pseudohyphae and true hyphae
The growth polymorphism
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)
Antifungals act on:
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
Antifungal drugs
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
