Medical Yeasts and Antifungal drugs

28 important questions on Medical Yeasts and Antifungal drugs

What is tinea capitis?

- Scalp ringworm
- Tinuea = fungal infection, capitis= scalp
- Fungal which eats hair follicles (there is ceratine in hair which is a protein, full of Nitrogen and Sulfur).
- When hit with UV fluorescent green (protects itself from ROS).

What is tinea circinata?

- Ringworm
- Round scaly lesion where the rim is more inflamed and scaly than the center.

What is tinea pedis and onychomycosis?

- Tinea pedis = feet (athlete's foot)
- Onychomycosis = nails
- Both very nutritious surfaces
- Trichophyton rubrum   
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What is superficial candidiasis?

Superficial infection with candida.
Oral candidiasis occurs often in immunocompromised patients.

What is candida auris?

- An emerging fungus
- causes invasive infections
- often multi-drug resistant
- resulting in hospital-acquired infection

What is the difference between pathogenic and opportunistic fungi?

Pathogenic fungi:
- Causes disease in both immunocompetent and  immunocompromised hosts
- Immunocompromised = presence debilitating disease or immunosuppressive drugs
- Not in the Netherlands
- Often through inhalation

Opportunistic fungi:
- Causes disease in immunocompromised hosts
- Rarely pathogenic in immunocompetent hosts, but can be life-threatening in immunocompromised host.
- Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans

What are the 2 main groups of fungi and what is the difference between them?

- Ascomycetes: form ascus (sac). Spores form inside the ascus.
Aspergillus fumigatus
Basiodiomycetes: form basidium. Cell 'pops out'.
Cryptococcus neoformans

They differ in their sexual cycle, during sporulation

What are Aspergillus fumigatus conidia?

- Asexual spores
- Normally broken down by lysosomes in macrophages
- Many fungi cannot withstand body temperature (37 C), however Aspergillus fumigatus are resistant to heat (mono-culture in compost hope).
- Can end up on transplants (spores) --> high mortality rate

What are candida albicans?

- White colonies on blood plates
- Can undergo a switch from yeast form to hyphal form (essential for virulence)
- Yeast form cells form germ tubes which can grow out
- Lives as commensal on the skin and on mucosa of GI tract.
- Can cause invasive systematic infections (life threatening in immunocompromised patients causing infections of liver, kidneys and brain)

What are the risk factors for candidiasis?

Use of:
- (broadspectrum) antibiotics
- immuno-suppressants
- catheters
- prosthetic devices
- abdominal surgery

Why can macrophages not deal with candida?

Candida has a defense against oxidative stress, morphological switch and uses the breakdown products of the lysosome as energy source for growth --> incubates within the macrophages.

- Candida has a strong cell wall to protect from lysosome and uses the breakdown products from lysosome as fuel.

Why is diabetes a risk factor for candidiasis?

- DmT2 is a risk factor because of the high glucose concentration of the blood (15-20 mM). The kidney cannot reabsorb all the glucose, which results in glucose in the urine. Glucose is a food source for candida.

Why is the use of antibiotics a risk factor for candidiasis?

Antibiotics kill gramm positive bacteria, so there will be more space to outgrow for candida species.

What would be a faster way to diagnose patients?

With PCR ribosomal DNA (very specific and just 1 hours instead of a couple days).

What are Cryptococcus neoformans?

- Very much alike with human cells; a lot of genes homologous to humans --> difficult to make drugs
- Capsule of carbohydrates (defense against immune system, makes it  difficult for phagocytosis).
- Only fungal with capsule!
- Defense mechanism: melanin (protects against ionizing radiation & oxidative damage by phagocytes) AND capsule (polysaccharides which secrete lipase when in phagolysosome --> can digest lysosome membrane).

What are virulence factors?

- Virulence factors: molecules expressed by pathogenic or opportunistic organisms that are important for causing disease in a host.
- Can be lipids, carbohydrates, or proteins. Form ideal targets of the development of antifungal drugs.

* Factors that are involved in in basic cellular metabolism (such as housekeeping proteins and structural components) are essential for survival of the microorganism in a host, but are not called virulence factors because they do not influence the host directly..

What are the virulence factors of Cryptococcus and how do they work?

1. Melanin:
- Synthesized from L-DOPA (precursor) by Laccase
- Protects against environmental stresses such as ionizing radiation AND oxidative damage by phagocytes.
- Phenol oxidase required for oxidation of L-DOPA (spontaneously through autooxidation)

2. Capsule:
The polysaccharides secretes lipase when in the phagolysosome, those can digest the lysosome membrane. The Cryptococcus then grows inside the cytoplasm and ruptures the host cell after 8-18 h of ingestion.

* Virulence factors allow C.Neoformans to reproduce inside macrophages, making it an intracellular parasite.

What is the mode of action of macrophages and neutrophils?

Phagosome --> fusion with lysosome --> phagolysosome

Oxygen-dependent mechanism:
- Reactive Oxygen/ Nitrogen species
- HOCl (hypochlorite, neutrophils)

Oxygen-independent mechanism:

- Hydrolytic enzymes (proteases & lipases)
- Defensins (basic micobicidal peptides)
- Nutrient deprivation

How does the identification and testing of virulence factors go?

1. Identification
2. Gene deletion (knock out)
3. Virulence essays with deletion strain
4. Virulence factor
5. Putative target for antifungal drug design

How does amphotericin B look like? And what does it do?

- Amphotericin B is a polyene. Its a therapy for systemic fungal infection. It has a hydrophilic side with hydroxyl groups and a hydrophobic side with double-bonds.

- Ampthotericin B interacts with Ergosterol in fungi. This forms a pore (hydrophobic side to ergosterol, hydrophilic to pore). --> ions like K+ and Mg2+ can leak --> death fungal cell
- Fungicidal

* Side effect: kidneys stop working

* Candicidin is the more soluble variant

What are azoles and how do they work?

- Azoles are heterocycles of carbon & nitrogen
- Miconazole is a diazole, fluconazole is a triazole (no activity against molds)
Fungistatic (patients need to take drug all the time)
- Inhibit fungal CYP51 by binding to it --> lanosterol cannot be converted into Ergosterol. This alters the structure and function of the plasma membrane.

What are the drawbacks of the current antifungals?

- Only a limited number of antifungal drugs are available
- Amphotericin B is (reversibly) nephrotoxic (toxicity kidneys)
- Resistance against azoles is increasing

Why is the cell wall a good target for the development of novel antifungal drugs?

The cell wall is needed for protection osmoses.

What is an ideal antifungal target?

- An enzyme that synthesizes a reaction product essential for viability of the fungal cell. Inhibition of the enzyme by an antifungal drug leads to lysis of the fungal cell.

- An enzyme that is specific for fungal cells and absent from human cells. This decreases chances of side effects of the antifungal drugs in patients.

Which structural polysaccharides does a fungal cell wall contain?

- a-glucan
- B-glucan:
B-glucan synthase uses UDP-glucose
- chitin:
Chitin synthase uses UDP-N-acetylglucosamine

* Each is synthesized by a specialized synthase
* Catalytic domains synthases are located intracellulary

What is the function of a-glucan?

- S.pompe: required for maintaining structural integrity
- Cryptococcus Neoformans: required for normal growth and capsule binding

What are the main differences between macrophages and neutrophils with respect to their ability to kill off intracellular foreign organisms?

- Neutrophils produces way more NADPH oxidases than macrophages:
NADPH oxidases also make ROS. (NADPH + 2O2 --> NADP + 2 O- + H+). O2 --> H202 --> OH. The ROS kill off the microorganisms.

- Neutrophils have myeloperoxidases which produce different radicals which are very reactive (HOCL, Hypochlorite).
* This heme-containing enzyme gives pus and phlegm the distinctive green tint.

What is the molecular mechanism of azoles?

- Azoles inhibit CYP51 which hiders the ergosterol synthesis.

- Oxygen is right between the heme group and the substrate. Azole binds to the iron. So, the Azole ring is interacting with the iron, instead of the O it is now the negative N. The inhibitor is a competitive inhibitor competing with the oxygen.

Oxidation:
Fully reduces --> aldehyde --> ketone --> acid group
Formic acid is being fomed. CYP51 slowly oxidized from 30 to 29 C. There are 3 oxygen needed because every step requited an oxygen and a NADPH.

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