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Infect & Immune 2 AW, DJT & ISB > ISB L2 Modes Of Action > Flashcards

ISB L2 Modes Of Action Flashcards

0
Q

Why is there less resistance from fungi?

A

Because fungi utilise sterols other than ergo sterols as the major component of their cell membrane so survival pressure does not build up

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1
Q

Why are more side effect expected with antifungal agents?

A

Fungi are eukaryotic like humans

Bacteria are prokaryotic

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2
Q

What antifungal was introduced in 1959 and quickly became gold standard

A

Griseofulvin

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3
Q

Mode of action of griseofulvin

A

To accumulate in the precursor keratin cells to prevent transmission of the fungi to the unexfolidate skin cells

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4
Q

What thing does griseofulvin actually interfere with?

What is it comprised of ….. and ……. which is assembled into ………… and ………….

A

Tubulin
Alpha and beta tubulin.

Assembled into microtubules and microfilaments

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5
Q

Function of micro tubules

A

Play a role in cilia and flagella and the internal architecture controlling mitosis.
Their assembly and disassembly is described as dynamic instability.

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6
Q

To what expect does griseofulvin interact with the components?

A

Reversibly and equally with both alpha and beta tubulin.

Reacts stoichiometrically with tubulin dimers and causes rapid depolymerisation of intact micro tubules.

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7
Q

Griseofulvin reacts at a site distinct from …… causing ……….

A

Colchicine binding site (anticancer)

Produces major conformational changes in the tubule protein preventing reassembly.

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8
Q

What are nyastin and amphotericin derived from?

A

The fungal broth of aspergillus nodosum

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9
Q

How are nyastin and amphotericin admin

A

IV

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10
Q

nyastin and amphotericin mode of action is based on their similarity to….

A

Alpha-helix, structure if 7TM receptor

Bind and form pores for membrane spanning channel permeation

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11
Q

Amphrericin B can be delivered via….

Amphotericin B exists as ……. In lipid bilayer

A

Liposomes.

Exists as a monomer in lipid bilayer and aggregation above (1:1000) causes leakage from the cells

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12
Q

3 antifungal classes that target the ergosterol bio synthetic pathway

A

Azoles
Allylamines
Morphilines

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13
Q

E.g. Of morpholines

A

Amorolfine

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14
Q

How do we know the ergosterol pathway is involved?

What gene was especially responsive?

A

Compare transcription profiles of strains containing deletions of late stage ergosterol genes.

ERG11 which controls CYP51A1 - P450 dependent 14-alpha-demethylase

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15
Q

Mode of action of amorolfine

A

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

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16
Q

What enzyme is higher in strains that make more ergosterol?

A

P450-dependent 14alpha (of lanosterol or mavelonate)

Increase in ergosterol biosynthesis coincides with decrease in susceptibility to azoles and amphotericin B.

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17
Q

Higher squalene activity means…

A

More terbinafine is needed to inhibit synthesis of 2,3 oxidosqualene from squalene

18
Q

What is the mammalian equivalent of ergosterol?

A

Cholesterol

19
Q

What is the structural difference between chol and ergosterol?

A

Double bond in ring B (7-8)

Double bond and extra C branching off the side chain at the top

20
Q

How were imidazole derivative made?

A

Screening program

21
Q

Miconazole and ketoconazole mode of action?

A

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)

22
Q

How come some candida is not susceptible to the direct membrane damage of ketoconazole?

A

Phenotypic changes during the growth cycle coincidentally confer resistances or susceptibility

23
Q

Are the antifungal effects of imidazoles dependent on growth phase?

A

No

24
Q

Miconazole is effective against…..

A

Fungi and some gram positive bacteria

25
Q

3 modes of action proposed for Miconazole funciton

A
  • interaction will cell wall
  • alteration of the permeability of the membrane
  • interference with the biosynthesis of ergosterol
26
Q

What is the initial target of Miconazole

A

Proposed that it is mitochondrial ATPase (at least during growth on nonfermentable carbon sources)

27
Q

Triazoles that can be used systemically? 2

A

Fluconazole and irracional ole

28
Q

Azoles are cidal or static?

A

Statics

29
Q

Major targets of azoles

A

P450 14alpha-demethylase
C4-demethylase

Which act on the conversion of lanosterol on the ergosterol bio synthetic route

30
Q

On what part does the azole bind?

A

On the heam (p450) iron.

the halogenated phenol sits deep inside the same hydrophobic binding cleft as the 17alky substrate, PI PI stacking.

31
Q

Allyamines mode of action??

A

No competative inhibitors of squalene epoxidases - intracellular levels of squalene build up as well as steroid biosynthesis being inhibited.

32
Q

Why do allylamines have fewer side effects?

A

Selectivity if achieves as lower affinity for mammalian squalene epoxidase

33
Q

Method of overcoming resistance?

A

Active efflux - use milbemycin as a pump inhibitors

34
Q

Mutation in squalene epoxidase reduces affinity for……

A

Azole and squalene

35
Q

What is the function of asparaginases?

A

Aid skin entry

36
Q

What is the role of keratinises?

A

Allow the use of dead skin cells for food

37
Q

Future developments will exploit fungus specific targets such as

A

Asparaginases
Keratinises
Fungal cell wall components

38
Q

Name there fungal cell wall components

A

Chitins
Mammans
Glucans

39
Q

Structure of nyastin and amphotericin

A

One side with many hydroxyls
One side with double bonds

So one is wants to be in lipids (ergosterol).
Amphiphilic - several form a poor from the poly OH face to let nutrients out.

41
Q

General imidazole structure

A

Five membered ring with 2N.
This strongly coordinates to Fe2+
(At the centre of fungal p450)

42
Q

Grisofluvin bond to

A

incorporated into DNA and interferes with production

43
Q

5flucytosine mode of action

A

inhibition of formation of useful steroid

increased concentration of starting material becomes toxic

44
Q

What shape does p450 fit

A

6 ring - 5 ring (whether or not it is on a steroid)
-loses methyl ring at C10 of AB rings on steroid
this can also inhibit breast cancer
—— see picutuers

Infect & Immune 2 AW, DJT & ISB (9 decks)

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