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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
Why is treating fungal infections challenging?
Drug toxicity | -> severe side effects
26
Increased anti fungal resistance | - threat to..?
Food security | Human health
27
2 evolutionary drivers of anti fungal resistance
Antifungal usage Pathogens
28
Evolutionary drivers of anti fungal resistance | - anti fungal usage
Intensive agriculture Increased immunocompromised humans Prophylactic usage (protect not cure) Lack of chemical diversity
29
Evolutionary drivers of anti fungal resistance | - Pathogens
Strong selection pressure (only a few anti-fungals) High recombination/mutation rates Global movement + dispersal
30
Evolution of azole resistance | - 4 main ways
1. Target mutation or over expression 2. Efflux pump over-expression 3. Altered cellular processes 4. Stress response
31
Evolution of azole resistance | -Target mutation or over expression
- alter cytochrome p450 so azole can't bind | - over-express cytochrome p450 so some enzyme remains uninhibited
32
Evolution of azole resistance | - efflux pump over expression
(Occurs in biofilms) Azole must get into cell to inhibit enzyme - if pumped out ASAP = reduces effects
33
Evolution of azole resistance | - Altered cellular process
Normally: Azole inhibits cytochrome p450 - > activates Erg3 - > produces toxic sterol intermediate - > fungus dies BUT mutation prevents toxic sterol production -> fungal can continue growing
34
Evolution of azole resistance | - Stress response
Membrane-induced stress responsive pathways e.g. calcium-calcineurin pathways Enables cell to tolerate anti-fungal -> resistance can they evolve via other mechanisms
35
Dual use of azoles in the clinic + the field
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
Efficacy tests | - disk diffusion assay
1. Cover agar in fungus 2. Put anti-fungal discs on top 3. Zones of inhibition form
37
Efficacy tests | - E-test
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
Efficacy tests | - MIC test
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
Problems with efficacy testing
> 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
New anti fungal drugs
Repurpose established medications - already know pharmacology + toxicology - can screen them for adjuvants
41
Adjuvants
= pharmacological or immunological agent that modifies the effect of other agents
42
Exploiting activated stress responses
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
Problem with antifungals reading cryptococcal meningitis
Poor penetration of CNS | - few fungistatic azoles show reasonable penetration
44
SRT anti-depressant
= potent inhibitor of C. neoformans (fungal meningitis) Synergistic with fluconazole Even greater reduction in brain fungal burden when treated using both
45
Nikkomycin Z
Produced by Streptomyces - inhibits production of chitin Competitive inhibitor of chitin synthase
46
Nikkomycin Z and Echinocandins
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
B-1,6-glucan inhibitors
Crucial component of fungal cell wall In vitro activity against range of Candida species
48
Impairing the emergence of drug resistance
Using Antifungal + inhibitor of Hsp90 or calcineurin Expand drugs available Target stress responses - enhances efficacy of azoles + echinocandins
49
Using Antifungal + inhibitor of Hsp90 or calcineurin
- more effective at killing pathogen | - harder for pathogen to evolve resistance to 2 compounds simultaneously

Infection and Immunology (13 decks)

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