Antifungal drugs
Difficulty of creating drugs?
The similarity of fungal and mammalian cells creates a number of challenges for designing drugs that are selectively toxic to fungal cells but not to our own cells.
The only significant difference between fungal and mammalian cells:
- presence of fungal cell walls
- a small structural difference in the plasma membrane
1. Fungal cell wall
Cell wall of most fungi is composed of
- mannoproteins
- rigid layers of complex polysaccharides
- β-1,3 and β-1,6-linked glucans
- chitin
Being external, the cell wall offers
- mechanical strength and acts as a barrier
- thus protecting the fungus from the hostile environment.
- lies the plasma membrane made up of phospholipid bilayer
- The major sterol found in fungal plasma membranes: ergosterol
- acts to maintain membrane integrity in the same capacity as cholesterol,
- cholesterol is the major sterol found in mammalian cell membranes
- houses multisubunit enzymes
- responsible for fungal cell wall construction.
2. Amphotericin B and Nystatin
Ergosterol is the target for many antifungal medications
Drug:
- Amphotericin B
- broad-spectrum anti-fungal drug
- works by binding to ergosterol in the fungal cell membrane and forming pores
- cause rapid leakage of intracellular ions
- fungal cell death
- also bind to cholesterol molecules found in human cell membranes
- although with relatively lower affinity
- lead to major adverse consequences
- because binding to cholesterol also leads to the formation of pores
- increase membrane permeability particularly in the renal vasculature and renal epithelial cells
- lead to nephrotoxicity
- Hence, Amphotericin B is typically reserved only for treatment of severe systemic infections that require a rapid response
- Nystatin
- binds to ergosterol causing leakage of intracellular components
- has the same mechanism of action as Amphotericin B, but more toxic
- because of that it is not used systemically
- also not absorbed from mucous membranes and skin
- largely limited to the treatment of superficial Candida infections of the mouth, skin, intestinal tract and vagina
3. Azoles and Allylamines
designed to target enzymes involved in ergosterol biosynthesis
Ergosterol biosynthesis in fungi
- utilizes a compound called squalene as a starting material
- In the presence of an enzyme called squalene epoxidase,
- squalene is transformed into lanosterol,
- In the presence of a cytochrome P450 enzyme called 14α-demethylase,
- lanosterol is subsequently converted to ergosterol
Azoles
- 14α-demethylase is the target
- Drugs:
- Clotrimazole
- Fluconazole
- Itraconazole
- Ketoconazole
- Miconazole
- Voriconazole
Allylamines
- target on fungal squalene epoxidase
- Drug:
- Naftifine
- Terbinafine
- Butenafine
- allylamine derivative drug
By inhibiting squalene epoxidase and 14α-demethylase,
- allylamines and azole antifungal agents deplete cell membrane ergosterol
- impairing membrane fluidity
- accumulation of toxic sterols
- fungal cell death
Both squalene epoxidase and 14α-demethylase are also present in human cells,
Although human enzymes are less affected than the fungal enzymes, there is still a potential for non-targeted inhibition, which can lead to many adverse effects.
One of the prime examples:
- non-targeted inhibition of human drug-metabolizing cytochrome P450 enzymes by azoles, which is responsible for many pharmacokinetic drug interactions.
4. Echinocandins
- Target on beta-glucan
- designed to target an enzyme located in the fungal plasma membrane that is responsible for the production of β(1-3)-glucans called β-(1,3)-glucan synthase
- inhibits β-glucan synthase
- leads to a decrease of β-glucans in the cell wall
- causing osmotic instability
- ultimately cell lysis.
Drug:
- Anidulafungin
- Caspofungin
- Micafungin.
Advantages
- activity against azole-resistant Candida strains & Aspergillus species.
- relatively low potential for toxicity or serious drug interactions
- because the enzyme system for beta-glucan synthesis is absent in human cells
5. Griseofulvin and Flucytosine
work by disrupting fungal cell division via mechanisms similar to cancer chemotherapeutic agents.
Griseofulvin
- binds to tubulin
- disrupting microtubule function
- inhibiting fungal cell mitosis
Flucytosine
- works at the nucleus level where it is converted into 5-fluorouracil
- then to other active metabolites that inhibit fungal RNA and DNA synthesis.
6. Reference
https://youtu.be/59aJJ6N2a3c
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