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Microbiota On Mucosal > C3 Antifungal Treatment > Flashcards

C3 Antifungal Treatment Flashcards

1
Q

Why are there only 3 classes licencesed for systemic anti fungal

A

Limited range of targets specific for fungi cell wall or some parts of membrane

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2
Q

Give an example of why systemic illness has risen

A

Increased chemotherapy and the 80s aids epidemic led to rise in oral candida

Aspergillus in. 90s

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3
Q

Since the aids epidemic, what emerging fungi has overtaken candida

A

Aspergillus fumigatus (invasive aspergillosis)

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4
Q

What are the 3 major diseases and how many people killed with them yearly

A

Cryptococcal meningitis/crypto - 1 mill
Systemic candidiasis - 400k
Aspergillosis- 700k

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5
Q

If you have aids with aspergillosis what is death rate - much higher for Immunocompromised

And what suppressive condition is associated with candida or cryptococcus death

A

86%

Candida- neutropenia
Cryptococcus - transplantation

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6
Q

What percentage of people with these systemic infections will die - v serious

A

Half of them

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7
Q

Give 2 targets of drugs which can’t be used for systemic infections / not licenced for systemic use

A

Microtubule synthesis
Dna/rna synthesis (flucytosine - for budding yeast)

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8
Q

What drugs can be used for dermatophytoses/skin infections like tinea pedis that target microtubules

A

Griseofulvin

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9
Q

Give the timeline of introduced 3 classes

A

Amphotericin B (polyenes) first late 50s

Azoles in 80s aids epidemic (flu con Azoles and itraconazoles first class)

Then early 2000s echinocandins

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10
Q

Has there been any new class since 2000s

A

Non

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11
Q

What is ampB polyene target

A

Ergosterol in pm needed to regulate fluidity so if disrupted causes cell stress

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12
Q

What shape do polyenes have which first suggested it acted as a pore to let Leakage out

A

Amphipathic molecule could help form a pore within pm

Has a hydrocarbon hydrophobic chain
And a polyhydroxyl hydrophilic chain

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13
Q

What do recent biochemical studies suggest instead

A

It acts as a sterol sponge sitting on top of membrane and absorbs sterol to cause fluidity

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14
Q

What shape does mode of action suggest how it’s more affinity to ergosterol thwn cholesterol in host

A

Cylindrical shape ergosterol vs sigmoidal cholesterol

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15
Q

What is the 2 main advantage and of polyenes

A

Broad spectrum use (aspergillus, candida and cryptocccus)

Also very limited resistance has been shown

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16
Q

What are the 2 main disadvantages of it

A

Only IV injection through drip = not accessible to developing countries

Also lack of specificity causes toxicity eg neohrotoxicity

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17
Q

Infusion related injections also have problems which suggest oral admin is beneficial. Explain

A

Hypomagneisum and other adverse effects like nephrotoxicity

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18
Q

Which 2 formulations alternative to natural Micelle form of ampb have been studied for oral admin not systemic

A

Liposomal ampb (inserted in liposome)

Cochleate insertioj

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19
Q

What are cochleates

A

Phospholipid-cation structures forming spiral lipid bilayers where ampb is inserted

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20
Q

When injecting mice with candida what did these formulas show

A

100% survival with cochleTe, 90% with l-amb and 70% natural ampb

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21
Q

Which one is now licensed

A

Liposomal (cochleate did not move from preclinical)
Ambisome is licenced for severe mycoses

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22
Q

What is still an issue with ambisome

A

Iv injection and still some nephrotxicity but less toxic

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23
Q

Which modified ampB cannot bind cholesterol had been in clinical trials but synthetic access isn’t good enough to licence

A

C2’ hydroxyl deletion

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24
Q

What are the 4 triazoles and what they work on

A

Fluconazole - ca,cu NOT AF
Itraconizole- same but works on dermatophytes too
Latest voriconazole (all 4)
Posaconazole - extended sp

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25
Q

What is their structure

A

5 side aromatic rings with 3N 2C (3N why they’re called triazoles)

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26
Q

What change to fluconazole makes voriconazole work on aspergillus

A

Extra methyl group

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27
Q

What is the target of triazoles

A

Also target ergosterol but they target it’s synthesis

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28
Q

Which enzyme in biosynthesis pathway do they bind AS of

A

Erg11/cyp51 lanosterol demethylase

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29
Q

What does it contain in active site that the N binds to and blocks

A

Iron ion in the iron protoporphyrin structure (heme like) in active site

30
Q

What happens instead

A

Get a precursor forming which is then converted by upstream erg3 enzyme to a sterol precursor causing fluidity disregulatiom

31
Q

In shat forms is it taken

A

Iv or orally

32
Q

Is it fungistatic or fungicidal like ampB

A

Fungistatic (making it more likely resistance)

33
Q

Other than being taken iv or oral and broad spectrum, what is another advantage over ampB

A

Not toxic

B-road spectrum voriconazole

Fluco taken as prophylactics

34
Q

Give an example where they are taken as prophylactics for immunosuppressive patients and how this can have adverse effects via drug-drug interactions

A

Patients taking calcineurin drug immunosuppressant eg transplant patients
Calcineurin metabolism due to cyp450 being targeted
Stay immunosuppressant for longer than wanted

35
Q

What are azoles used for in agriculture which can impact more on resistance

A

Crop sprayed with azoles so more resistant exposed strains can infect humans

36
Q

Why would being fungistatic cause resistance during infection too

A

Adaptation mutations can occur

37
Q

Other than resistance and adverse drug-drug what are the disadvantages

A

Hard to maintain plasma levels

Birth defect issues have been reported

38
Q

Which water based prodrug of isavuconazole now licenced and why is it better

A

Isavuconazovium sulfate

Prolonged elimination half life to maintain plasma levels

39
Q

What is the strucrure of echinocandins

A

Lipopeptides
Hexa peptide core with lipid side chain

40
Q

What does it work for and give examples

A

Micafungin, caspofungin

Asp (licensed 2001) and candidiasis (2003 licensed)

(not cryptocccus)

41
Q

What is it’s target

A

B1,3 glucan synthetase which it blocks

Causing cellular stress

42
Q

Is the mechanism known for blocking action

A

No but likely competitive inhibition

43
Q

How was it found

A

Random screening in the 70s

44
Q

When was it approved

A

Early 2000s

45
Q

Why is it the safest class in terms of toxicity

A

Targeting cell wall so specific

46
Q

Is there resistance and what is the issue with the drug for broad action

A

Yes , some emerging strains with resistance bc used often but very limited resistance is found

(also doesn’t work for crypto and emerging species like fusarium)

47
Q

Why could aspergillus eventually develop resistance to it

A

Only fungistatic against it

48
Q

What type of admin is it

A

Iv- not available in all areas

49
Q

What is primary and secondary resistance and example of intrinsic

A

Primary is intrinsic, naturally resistant even without drug exposure

Eg candida krusei and glabrata to azoles - commonly isolated from aids patients

Secondary is acquired resistance eg from too much azoles

50
Q

Which 2 efflux pumps important in overexpression mediated resistance to drugs like candida strains (efflux is a mechanism of resistance)

A

Cdr1/2 abc transporters (use atp)

Mdr1 efflux pump (uses membrane potential not atp)

51
Q

How is overexpression achieved through tf

A

Gof transcription factors mutations

mrr1 for mdr1 efflux pump

Or tac1 for cdr1/2

52
Q

Where are these resistant strains of candida being seen growing whcih is the serious issue

A

AIDS or immunocompromosied

53
Q

Why would treatment with azoles induce these changes

A

Causes a fitness advantage and the mutation is selected for in tac1 or mrr1.

Selection for these Gof mutations

54
Q

How does c glabrata show resistance intrinsically through efflux pimps to azoles

A

Has a tf which a xenobiotic binding domain - binds azoles (pdr1/3) which when bound to drug will recruit machinery for txn of the efflux pumps like cdr1
Eg rna polymerase

Gof mutations in c glabrata means xbd can do this even better so drug never accumulated

55
Q

Give example of how a less common drug influx alteration mechanisms can cause resistance eg to azoles

A

Tac1 (Gof in some candida) mediated overexpression of pdr16 for phospholipid synthesis (phosphoinositol transfer protein)

Mediates a different composition of plasma membrane affecting drug uptake and also shown to influence drug efflux cdr1 potentially optimising its activity

56
Q

Point mutations in which enzyme have been reported to affect affinity of azoles to work - (3rd mech of resistance is alterations to target)

A

Erg11/cyp51

57
Q

Which specific mutation affects accessibility of the as of erg11 to azoles and which other point mutations found too

A

Phe105-leu

Others include in the heme binding domain which would affect N binding

58
Q

Which other enzyme in this pathway can be affected by resistance mutations

A

Erg3 where mutations affect its ability to convert precursor 14- methylfecosterol to an unusual sterol causing permeability

14 methylfecosterol supports continuous growth / no altered fluidity

59
Q

Why would these alterations be common in aids/Immunocompromised patients

A

Given fluconazole as prophylactics and they are fungistatic

60
Q

Why would gene amplification eg through trisomy for chr5 affect resistance in candida strains

A

It’s where tac1 for cdr1 efflux pumpvlocsted
And also where erg11 is located (less competitive inhibition if more of it)

61
Q

Give the reason echinocandins resistance can occur intrinsically in some candida isolates and give evidence

A

Mutations within the fks1 glucan synthetase in 2 hotspots which reduces drug sensitivity to fks1

Injection Into mice with fks1 mutants were not sensitive to drugs

62
Q

Which combination treatment used for cryptococcal meningitis and why - advancement in treatment

A

Flucytosine and ampB
Both too toxic to be given separately

63
Q

How does flucytosine work

A

Converged to 5fluorouracil which causes rna miscoding and also stops dna synthesis

64
Q

Which improvement to echinocandins is in development

A

Scy-078
It is oral based fks1 inhibitor instead of iv

65
Q

What sort of vaccines been used for candidiasis in model animals

A

B-mannan polysach and sap2 vaccines

66
Q

Which hsp could be targeted in future somehow (currently being studied with combo of azole use eg fluconazole) and why

A

Hsp90- reports that it can abrogate erg3 mediated Candida albicans resistance to azoles and also changes azoles from fungistatic to fungicidal if disrupted for af and ca

67
Q

Why is it still hard to find drugs for it

A

Not specific enough for it to not target our hsp - toxic effects when you inhibit host hsp90-

Need the development or fungal-selective hsp90 inhibitors instead

68
Q

Why could gpi biosynthesis pathways be targets in future

A

Found defects/downreg in gpi biosynthesis can disrupt cell wall composition in fungi, disrupt their morphology or even cause cell death (in Af)
gpi proteins like als 1 and 5 are potent adhesins important for cell binding and subsequent invasion

Eg af and ca.

69
Q

Give example of very rare polyene resistance issues

A

Altered pm membrane content such as reduced ergosterol content

70
Q

Which ampB is in development currently with better specificity to fungal sterols so less toxic

A

AmpB methyl urea

71
Q

What is currently being done / developed for improvement to cyp450 interference with azoles

A

Tetrazoles

72
Q

What small molecule screened to be an inhibitor of fungal gpi biosynthesis requiring protein gwt1 when administered in sub lethal concentrations can elevate immune responses to CA due to increased b1,3 glucan exposure - promising for future drugs

A

Gepinacin

Microbiota On Mucosal (22 decks)

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