C3 Antifungal Treatment Flashcards by Anna Safrankova

Why are there only 3 classes licencesed for systemic anti fungal

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

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Give an example of why systemic illness has risen

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

Aspergillus in. 90s

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Since the aids epidemic, what emerging fungi has overtaken candida

Aspergillus fumigatus (invasive aspergillosis)

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

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

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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

86%

Candida- neutropenia
Cryptococcus - transplantation

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

Half of them

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

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

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

Griseofulvin

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Give the timeline of introduced 3 classes

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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Has there been any new class since 2000s

Non

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What is ampB polyene target

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

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

Amphipathic molecule could help form a pore within pm

Has a hydrocarbon hydrophobic chain
And a polyhydroxyl hydrophilic chain

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What do recent biochemical studies suggest instead

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

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

Cylindrical shape ergosterol vs sigmoidal cholesterol

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What is the 2 main advantage and of polyenes

Broad spectrum use (aspergillus, candida and cryptocccus)

Also very limited resistance has been shown

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What are the 2 main disadvantages of it

Only IV injection through drip = not accessible to developing countries

Also lack of specificity causes toxicity eg neohrotoxicity

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

Hypomagneisum and other adverse effects like nephrotoxicity

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

Liposomal ampb (inserted in liposome)

Cochleate insertioj

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What are cochleates

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

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When injecting mice with candida what did these formulas show

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

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Which one is now licensed

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

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What is still an issue with ambisome

Iv injection and still some nephrotxicity but less toxic

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

C2’ hydroxyl deletion

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What are the 4 triazoles and what they work on

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

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What is their structure

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

What change to fluconazole makes voriconazole work on aspergillus

Extra methyl group

What is the target of triazoles

Also target ergosterol but they target it’s synthesis

Which enzyme in biosynthesis pathway do they bind AS of

Erg11/cyp51 lanosterol demethylase

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

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

What happens instead

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

In shat forms is it taken

Iv or orally

Is it fungistatic or fungicidal like ampB

Fungistatic (making it more likely resistance)

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

Not toxic B-road spectrum voriconazole Fluco taken as prophylactics

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

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

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

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

Why would being fungistatic cause resistance during infection too

Adaptation mutations can occur

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

Hard to maintain plasma levels Birth defect issues have been reported

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

Isavuconazovium sulfate Prolonged elimination half life to maintain plasma levels

What is the strucrure of echinocandins

Lipopeptides Hexa peptide core with lipid side chain

What does it work for and give examples

Micafungin, caspofungin Asp (licensed 2001) and candidiasis (2003 licensed) (not cryptocccus)

What is it’s target

B1,3 glucan synthetase which it blocks Causing cellular stress

Is the mechanism known for blocking action

No but likely competitive inhibition

How was it found

Random screening in the 70s

When was it approved

Early 2000s

Why is it the safest class in terms of toxicity

Targeting cell wall so specific

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

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)

Why could aspergillus eventually develop resistance to it

Only fungistatic against it

What type of admin is it

Iv- not available in all areas

What is primary and secondary resistance and example of intrinsic

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

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

Cdr1/2 abc transporters (use atp) Mdr1 efflux pump (uses membrane potential not atp)

How is overexpression achieved through tf

Gof transcription factors mutations mrr1 for mdr1 efflux pump Or tac1 for cdr1/2

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

AIDS or immunocompromosied

Why would treatment with azoles induce these changes

Causes a fitness advantage and the mutation is selected for in tac1 or mrr1. Selection for these Gof mutations

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

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

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

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

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

Erg11/cyp51

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

Phe105-leu Others include in the heme binding domain which would affect N binding

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

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

Why would these alterations be common in aids/Immunocompromised patients

Given fluconazole as prophylactics and they are fungistatic

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

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

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

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

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

Flucytosine and ampB Both too toxic to be given separately

How does flucytosine work

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

Which improvement to echinocandins is in development

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

What sort of vaccines been used for candidiasis in model animals

B-mannan polysach and sap2 vaccines

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

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

Why is it still hard to find drugs for it

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

Why could gpi biosynthesis pathways be targets in future

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.

Give example of very rare polyene resistance issues

Altered pm membrane content such as reduced ergosterol content

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

AmpB methyl urea

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

Tetrazoles

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

Gepinacin