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Infection and Immunology > Disease control > Flashcards

Disease control Flashcards

1
Q

4 major anti-fungal classes + their targets

A

Azoles
- cell membrane integrity

5-flucytosine
- Nucleic acid (DNA/RNA) synthesis

Polyenes
- cell membrane integrity

Echinocandins
- cell wall synthesis

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2
Q

Why is it difficult to treat fungal infections?

A

Fungi are more closely related to animals than bacteria

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3
Q

Polyene

- mechanism of action

A

Targets cell membrane by disrupting stability

Intercalates with ergosterol in cell membrane

  • > creates K+ channel
  • > cell contents leak out
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4
Q

Polyene

  • produced by
  • type of anti-fungal
A

Streptomyces

Fungicidal

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5
Q

Polyene

- usage

A

Amphotecerin B

Used to treat Cryptococcosis

BUT has renal toxicity (kidneys)

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6
Q

Azoles

- mechanism of action

A

Inhibits ergosterol biosynthesis

Targets Cytochrome P450 enzyme (lanosterol 14-alpha-demethylase)

Accumulation of toxic sterol intermediates

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7
Q

Azoles

- anti-fungal type

A

Fungistatic

  • requires functioning immune system to achieve max therapeutic effect
  • needs to clear the infection
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8
Q

Azoles

- application

A

In Fluconazole

Used for yeast infections

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9
Q

Azoles

  • Voriconazole
  • mechanism of action
A

Synthetic derivative of fluconazole

Binds tighter to lanosterol demethylase

Inhibits a 2nd enzyme in same pathway

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10
Q

Azoles

  • Voriconazole
  • type of anti-fungal
A

Fungicidal

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11
Q

Azoles

  • Voriconazole
  • application
A

Fungicidal activity on par with Amphotericin B (polyene)

Active against opportunistic moulds (Aspergillus)

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12
Q

5- Flucytosine

- mechanism of action

A

Anti-metabolite
- fluorinated pyrimidine

Blocks DNA synthesis + protein translation

Taken into cell ->Metabolised by fungal cytosine deaminase
-> becomes toxic

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13
Q

5-Flucytosine

- type of anti-fungal

A

Fungicidal

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14
Q

5-Flucytosine

- why don’t humans accumulate the toxic intermediate?

A

Don’t have the enzyme

- cytosine deaminase

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15
Q

5-Flucytosine

- application

A

Fungicidal activity inferior to Amphotericin B (polyene)

Alternative mono-therapy fo patients with fluconazole-resistant Candida sp.

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16
Q

Echinocandins

e. g. Caspofungin
- mechanism of action

A

Lipopeptides

Non-competitive inhibition of B -1,3 - glucan synthase in cell wall required for production of cell wall polysaccharides

Blocks cell wall synthesis

Fungal cells lose shape
+ become osmotically fragile

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17
Q

Echinocandins

- why does it not affect human cells?

A

B-1,3-glucans not present in humans

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18
Q

Echinocandins

- type of anti-fungal

A

Fungicidal against yeast + C. albicans

Fungistatic against moulds (A. fumigatus)

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19
Q

Echinocandins

- not functional against

A

C. neoformans

= basidiomycete
- less B-1,3- glucans

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20
Q

Anti-fungal paradoxical effect

A

Phase 1 = low AF conc
- high absorbance

Phase 2 = x10 AF conc
- low absorbance

Phase 3 = x10 AF conc
- high absorbance

Phase 4 = x10 AF conc
- low absorbance

21
Q

Why does the anti-fungal paradoxical effect occur?

A

In phase 3

  • induces other stress-response pathways
  • > changing of the cell wall
22
Q

2 cell wall stress signalling pathways

A

Cell wall integrity pathway (MAPK)

Calcium- calcineurin pathway

23
Q

Cell wall stress signalling pathways

  • role
  • what are they activated by?
A

Cross-talk between pathways

Control cell wall remodelling

Activated by fungal cell wall stress

24
Q

Cell wall stress signalling pathways

- what do these contribute to?

A

Paradoxical effect

Virulence and anti-fungal resistance

25
Q

Why is treating fungal infections challenging?

A

Drug toxicity

-> severe side effects

26
Q

Increased anti fungal resistance

- threat to..?

A

Food security

Human health

27
Q

2 evolutionary drivers of anti fungal resistance

A

Antifungal usage

Pathogens

28
Q

Evolutionary drivers of anti fungal resistance

- anti fungal usage

A

Intensive agriculture

Increased immunocompromised humans

Prophylactic usage (protect not cure)

Lack of chemical diversity

29
Q

Evolutionary drivers of anti fungal resistance

- Pathogens

A

Strong selection pressure (only a few anti-fungals)

High recombination/mutation rates

Global movement + dispersal

30
Q

Evolution of azole resistance

- 4 main ways

A
  1. Target mutation or over expression
  2. Efflux pump over-expression
  3. Altered cellular processes
  4. Stress response
31
Q

Evolution of azole resistance

-Target mutation or over expression

A
  • alter cytochrome p450 so azole can’t bind

- over-express cytochrome p450 so some enzyme remains uninhibited

32
Q

Evolution of azole resistance

- efflux pump over expression

A

(Occurs in biofilms)

Azole must get into cell to inhibit enzyme
- if pumped out ASAP
= reduces effects

33
Q

Evolution of azole resistance

- Altered cellular process

A

Normally: Azole inhibits cytochrome p450

  • > activates Erg3
  • > produces toxic sterol intermediate
  • > fungus dies

BUT mutation prevents toxic sterol production
-> fungal can continue growing

34
Q

Evolution of azole resistance

- Stress response

A

Membrane-induced stress responsive pathways
e.g. calcium-calcineurin pathways

Enables cell to tolerate anti-fungal
-> resistance can they evolve via other mechanisms

35
Q

Dual use of azoles in the clinic + the field

A

e.g. A.fumigatus

  1. Farmers spray anti-fungals on crops
    (not directly at A.f but they’re still exposed)
    -> selecting for increasingly resistant A.f in nature
  2. Immunocompromised person breathes in A.f from nature
    - some susceptible + some resistant
  3. Treated with azole fungicides (same function as in agri)
    -> removes susceptible population
  4. Resistant population remains
    -> treatment fails
    = high mortality rate
36
Q

Efficacy tests

- disk diffusion assay

A
  1. Cover agar in fungus
  2. Put anti-fungal discs on top
  3. Zones of inhibition form
37
Q

Efficacy tests

- E-test

A

Anti-fungal strips lay on fungus
- Has a gradient of anti-fungal concentrations

Enables you to identify conc of anti-fungal needed to inhibit growth

38
Q

Efficacy tests

- MIC test

A

Most accurate + laborious

Min conc of an anti fungal required to prevent the in vitro growth of yeast or moulds

MIC50 = lowest conc capable of inhibiting growth of 50% of population

MIC90 = 90% of population

39
Q

Problems with efficacy testing

A

> need to be standardised across institutions
- comparable

> need to culture fungus
- time consuming

> can be disastrous in clinical setting
- patient remains in critical condition

40
Q

New anti fungal drugs

A

Repurpose established medications

  • already know pharmacology + toxicology
  • can screen them for adjuvants
41
Q

Adjuvants

A

= pharmacological or immunological agent that modifies the effect of other agents

42
Q

Exploiting activated stress responses

A
  1. Treat fungus with fluconazole (azole)
  2. Induces cell wall integrity MAPK and calcium-calcineurin pathways
  3. Screened pathways for compounds that can inhibit these pathways
  4. Found multiple anti-cancer and immunosuppressant drugs that can inhibit pathways
43
Q

Problem with antifungals reading cryptococcal meningitis

A

Poor penetration of CNS

- few fungistatic azoles show reasonable penetration

44
Q

SRT anti-depressant

A

= potent inhibitor of C. neoformans (fungal meningitis)

Synergistic with fluconazole

Even greater reduction in brain fungal burden when treated using both

45
Q

Nikkomycin Z

A

Produced by Streptomyces
- inhibits production of chitin

Competitive inhibitor of chitin synthase

46
Q

Nikkomycin Z and Echinocandins

A

Nikkomycin Z synergistic with echinocandins
(B-1,3-glucan synthase inhibitor)

When used together = v good control of ascomycetes

= good broad-spectrum drug combination

47
Q

B-1,6-glucan inhibitors

A

Crucial component of fungal cell wall

In vitro activity against range of Candida species

48
Q

Impairing the emergence of drug resistance

A

Using Antifungal + inhibitor of Hsp90 or calcineurin

Expand drugs available

Target stress responses
- enhances efficacy of azoles + echinocandins

49
Q

Using Antifungal + inhibitor of Hsp90 or calcineurin

A
  • more effective at killing pathogen

- harder for pathogen to evolve resistance to 2 compounds simultaneously

Infection and Immunology (13 decks)

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