Lecture C4 - Anti-fungal Drugs Flashcards
How many classes of licensed antifungals are there to treat systemic infections?
3 because of selectivity. Fungal cells can be similar to human cells and a lot of processes are the same so if you target fungal processes you may also target human host cells.
Where do antifungals mainly target?
Fungal cell membrane or cell wall.
Name some antifungals and what they target.
Azoles - target sterols, the biosynthesis in the ER.
Echinocandins - target polysaccharide cell wall.
Polyenes - binds to steroid molecules associated with the plasma membrane of fungal cells.
Describe polyenes and give an example.
Example = Amphotericin B.
Binds to ergosterol in fungal membrane ‘sterol sponge’ and perturbs membrane function.
Specificity related to structural differences in fungal and human sterols and fungal cells having a higher sterol content in their membranes.
Kills the fungal cell.
What are the pros and cons of polyenes?
Pro - broad spectrum
Con - selectivity is low and can cause toxicity. Only administered systemically.
What are the effective oral routes for administering amphotericin B?
Liposome - drug combined with lipids.
Cochleate - phospholipid, cation containing crystallised structure that the drug can intercalate into the spiral lipid bilayer.
What does AM-2-19 do?
Kills fungi but spares kidney cells.
Structural derivative of AmB that does not bind cholesterol so prevents renal toxicity.
Describe triazoles and give an example.
Largest class of antifungals in use.
Example = Fluconazole.
Inhibits steroid formation - ergosterol depleted and replaced with unusual sterols which alters the normal permeability/fluidity of the cell membrane.
By adding a methyl group to fluconazole then it can also treat aspergillum fumigatus.
What is the molecular target of triazoles?
Erg11/Cyp51 which catalyses the oxidative removal of the 14 methyl group of lanesterol.
What is the mode of action of triazoles?
Erg11 contains an iron protoporphyrin moiety - triazoles bind tot he iron via the nitrogen in the triazole ring, blocking the active site of the enzyme and preventing its function.
Typically fungi-static - does not kill the fungus but stops it from working.
What are the pros and cons of triazoles?
Pros - non-toxic, prophylaxis treatment with fluconazole reduces the incidence of system infections in immunocompromised patients, oral triazoles are more accessible, broad acting.
Cons - resistance to azaleas is common, adverse drug-drug interactions due to interference with hepatic and intestinal cytochrome P-450 enzymes, difficult to control plasma levels of the drugs.
Describe echinocandins and give an example.
Example = Caspofungin.
Target beta-1,3 gluten synthase - Fks1, regulates synthesis of cell wall Beta-1,3 gluten polysaccharides.
Blocks Fks1 to block the synthesis of beta-1,3 gluten synthase so the cell wall can’t be built properly.
What are the pros and cons of echinocandins?
Pros - low frequency of toxicity - safest class of antifungals, low frequency of fungal resistance.
Cons - no activity against cryptococcus neoformans and emerging pathogens such as fusarium, only fungistatic against aspergillum species, only administered via IV.
What are the 2 forms of resistance?
Primary resistance - intrinsic, occurs in organisms never exposed in that host to the drug of interest.
Secondary - acquired, arises after exposure to the drug, more common.
Describe resistance to azoles.
Because azoles do not kill the fungal cells.
Most C auris isolates are azole reistant, C krusei and C glabrata are intrinsically resistant and increasingly being isolated from patients undergoing immunosuppressant therapies.
