ISB L2 Modes Of Action Flashcards
(44 cards)
Why is there less resistance from fungi?
Because fungi utilise sterols other than ergo sterols as the major component of their cell membrane so survival pressure does not build up
Why are more side effect expected with antifungal agents?
Fungi are eukaryotic like humans
Bacteria are prokaryotic
What antifungal was introduced in 1959 and quickly became gold standard
Griseofulvin
Mode of action of griseofulvin
To accumulate in the precursor keratin cells to prevent transmission of the fungi to the unexfolidate skin cells
What thing does griseofulvin actually interfere with?
What is it comprised of ….. and ……. which is assembled into ………… and ………….
Tubulin
Alpha and beta tubulin.
Assembled into microtubules and microfilaments
Function of micro tubules
Play a role in cilia and flagella and the internal architecture controlling mitosis.
Their assembly and disassembly is described as dynamic instability.
To what expect does griseofulvin interact with the components?
Reversibly and equally with both alpha and beta tubulin.
Reacts stoichiometrically with tubulin dimers and causes rapid depolymerisation of intact micro tubules.
Griseofulvin reacts at a site distinct from …… causing ……….
Colchicine binding site (anticancer)
Produces major conformational changes in the tubule protein preventing reassembly.
What are nyastin and amphotericin derived from?
The fungal broth of aspergillus nodosum
How are nyastin and amphotericin admin
IV
nyastin and amphotericin mode of action is based on their similarity to….
Alpha-helix, structure if 7TM receptor
Bind and form pores for membrane spanning channel permeation
Amphrericin B can be delivered via….
Amphotericin B exists as ……. In lipid bilayer
Liposomes.
Exists as a monomer in lipid bilayer and aggregation above (1:1000) causes leakage from the cells
3 antifungal classes that target the ergosterol bio synthetic pathway
Azoles
Allylamines
Morphilines
E.g. Of morpholines
Amorolfine
How do we know the ergosterol pathway is involved?
What gene was especially responsive?
Compare transcription profiles of strains containing deletions of late stage ergosterol genes.
ERG11 which controls CYP51A1 - P450 dependent 14-alpha-demethylase
Mode of action of amorolfine
Blocks delta14 reduction and delta7-8 isomerisation.
Results in depletion of ergosterol and accumulation of ignosterol in fue gal cytoplastmic membrane.
Fungal walls become thinker and chitin deposits formed inside and outside the cell walls
What enzyme is higher in strains that make more ergosterol?
P450-dependent 14alpha (of lanosterol or mavelonate)
Increase in ergosterol biosynthesis coincides with decrease in susceptibility to azoles and amphotericin B.
Higher squalene activity means…
More terbinafine is needed to inhibit synthesis of 2,3 oxidosqualene from squalene
What is the mammalian equivalent of ergosterol?
Cholesterol
What is the structural difference between chol and ergosterol?
Double bond in ring B (7-8)
Double bond and extra C branching off the side chain at the top
How were imidazole derivative made?
Screening program
Miconazole and ketoconazole mode of action?
Inhibit ergosterol synthesis (essential component of the fungal cell membrane)
Also Miconazole can exert direct physiochemical cell membrane damage at relearn felt high levels (although the same concentration of antifungal is needed)
How come some candida is not susceptible to the direct membrane damage of ketoconazole?
Phenotypic changes during the growth cycle coincidentally confer resistances or susceptibility
Are the antifungal effects of imidazoles dependent on growth phase?
No
