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Fungal Pathogens III Flashcards

1
Q

Fungal resistance is not as big a problem as antibiotic resistance because

A

Fungi do not have horizontal gene transfer

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2
Q

Types of antifungal agents

A
  1. Membrane disrupting agents (polyenes)
  2. Ergosterol synthesis inhibitors (azoles, allylamines)
  3. DNA synthesis inhibitors (flucytosine)
  4. Glucan synthesis inhibitors (echinocandins)
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3
Q

Why are there so few antifungals?

A
  1. Fungi are eukaryotes so closely related to our cells

2. Antifungals are very difficult to get into fungi (cell wall and efflux pumps)

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4
Q

Polyenes

A

Membrane disrupting agents
Associate with ergosterol to form pores
Leak cations Na and Ca
Nystatin and Amphotericin B

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5
Q

Ergosterol is the fungal equivalent of

A

Cholesterol

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6
Q

Polyenes can be toxic due to them binding to

A

Human cholesterol

Ergosterol and cholesterol structures very similar

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7
Q

Nystatin is used for

A

Superficial infections

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8
Q

Amphotericin B is used for

A

Systemic infections

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9
Q

Amphotericin B problems

A

IV use only

Nephrotoxicity (kidneys)

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10
Q

Polyenes have

A

A wide spectrum

Candida, cryptococcus, aspergillus

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11
Q

Azoles are the

A

Largest group of antifungals (5)

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12
Q

Azole refers to the

A

5 membered heterocyclic ring (Nitrogens)

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13
Q

Imidazole has

A

2 N, rarely used, toxic

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14
Q

Triazole has

A

3 N, commonly used

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15
Q

Azoles inhibit

A

Ergosterol synthesis

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16
Q

Azoles block the

A

14 alpha sterol demethylase (enzyme that demethylates lanosterol)
Blocks haem iron in the enzyme

Alters membrane fluidity (rigid)as alpha sterols build up

FUNGISTATIC - blocks growth but does not kill them

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17
Q

Azoles stop the demethylation of

A

Lanosterol

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18
Q

14 alpha sterol demethylase demethylates

A

Lanosterol

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19
Q

Azoles have a

A

Broad spectrum

Except - fluconazole, does not work on aspergillus

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20
Q

Azoles are mainly

A

Fungistatic

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21
Q

Azoles problems

A
  1. Drug interactions:
    - target enzyme related to cytochrome P450
    - can block human P450 in the liver so affect drug metabolism of other drugs
  2. Resistance
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22
Q

Allylamines inhibit

A

Ergosterol biosynthesis - squalene epoxidase

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23
Q

Allylamines cause cells to

A

Accumulate squalene which is toxic

24
Q

Accumulation of squalene is

A

Fungicidal

25
Q

Allylamines are most effective against

A

Dermatophytes

limited use in candida, aspergillus and cryptococcus

26
Q

5 flucytosine (5FC) is a

A

Synthetic analogue of cytosine

27
Q

5FC enters cells through

A

Cytosine permease (enzyme in cell wall)

28
Q

5FC is converted by cytosine deaminase to

A

5 Fluoroucil (5FU)

29
Q

5FC inhibits

A

Protein and DNA synthesis

30
Q

5FU gets incorporated into

A

mRNA

The ribosome cannot read it

31
Q

5FC only works against

A

Yeasts
Candida and cryptococcus

(filamentous fungi lack cytosine permease and cytosine deaminase)

32
Q

5FC problems

A

Resistance is very common

Not used as a single agent and never in candida

33
Q

Echinocandins are

A

Semi synthetic (developed in 2000’s)

34
Q

Echinocandins inhibit

A

Beta 1,3 glucan synthase

essential component of cell wall

35
Q

Echinocandins can be either fungistatic or fungicidal

A

Fungicidal in candida
Fungistatic in aspergillus
Not effective in cryptococcus

36
Q

Echinocandins good things

A

No problem of cross resistance

Low toxicity

37
Q

Echinocandins problems

A

Not effective against cryptococcus
IV use only
Expensive

38
Q

Treating superficial infections

A

Dermatophytes - allylamines

Candida - Azoles

39
Q

Treating systemic infections

A

Azoles
Amphotericin B (IV)
Echinocandins (IV)

40
Q

Mechanisms of resistance

A
  1. Primary/Natural

2. Secondary/Aquired

41
Q

Primary/Natural resistance

A

Intrinsic resistance linked to species or strain
(Allylamines not effective against candida)
(Fluconazole intrinsically not effective against cryptococcus)

42
Q

Secondary/Aquired resistance

A

Susceptible strain becomes resistant

Mutation and selection

43
Q

Resistance to Amphotericin B is

44
Q

Mechanism of Amp B resistance

A
  1. Reduced/alteration of ergosterol content
  2. Alteration of sterol/phospholipid balance
  3. Increased catalase activity (combat oxidative stress associated with amphotericin exposure)
45
Q

Resistance to Flucytosine

A

Primary ( ALL filamentous fungi)
(10% of candida)

Secondary (monotherapy, 30% candida resistant after treatment)

46
Q

Flucytosine mechanism of resistance

A
  1. Loss of permease activity
  2. Loss of cytosine deaminase activity
  3. Decrease in the activity of uracil phosphoribosyl-transferase

Partial resistance to 5FU is achieved through blocking action in mRNA

Mutations

47
Q

Resistance to Echinocandins

A

Primary - cryptococcus

Secondary - rare

48
Q

Echinocandin mechanism of resistance

A

Point mutations in beta 1,3 glucan synthase

Upregulated chitin synthesis

49
Q

Resistance to azoles

A

Primary - aspergillus, cryptococcus

Secondary - candida, common in HIV

50
Q

Azole resistance mechanism

A
  1. Reduced accumulation of azole (overexpression of efflux pumps)
  2. Alteration of target enzyme (point mutations decrease affinity of azole)
  3. Upregulate ERG11 (need more drug to compete)
  4. Alterations in sterol synthesis - blocking methylation (causes dual resistance to azoles and polyenes)
51
Q

ERG11

A

Ergosterol biosynthesis

52
Q

Mechanisms of resistance can be

A

Cumulative/additive

53
Q

The 4 classes of antifungal agents

A
  1. Azoles
  2. Polyenes
  3. Echinocandins
  4. Flucytosine
54
Q

Limitations of antifungals

A

Interactions
Toxicity
Resistance
Cost and availability

55
Q

Resistance is common with

A

Flucytosine

56
Q

Resistance is rare with

A

Azoles, polyenes, echinocandins

Medical & General Microbiology (24 decks)

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