Medical Yeasts and Antifungal drugs
28 important questions on Medical Yeasts and Antifungal drugs
What is tinea capitis?
- 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?
- Round scaly lesion where the rim is more inflamed and scaly than the center.
What is tinea pedis and onychomycosis?
- Onychomycosis = nails
- Both very nutritious surfaces
- Trichophyton rubrum
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What is superficial candidiasis?
Oral candidiasis occurs often in immunocompromised patients.
What is candida auris?
- causes invasive infections
- often multi-drug resistant
- resulting in hospital-acquired infection
What is the difference between pathogenic and opportunistic 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?
Aspergillus fumigatus
- Basiodiomycetes: form basidium. Cell 'pops out'.
Cryptococcus neoformans
They differ in their sexual cycle, during sporulation
What are Aspergillus fumigatus conidia?
- 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?
- 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?
- (broadspectrum) antibiotics
- immuno-suppressants
- catheters
- prosthetic devices
- abdominal surgery
Why can macrophages not deal with candida?
- 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?
Why is the use of antibiotics a risk factor for candidiasis?
What would be a faster way to diagnose patients?
What are Cryptococcus neoformans?
- 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?
- 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?
- 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?
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?
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?
- 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?
- 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?
- 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?
What is an ideal antifungal target?
- 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?
- 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?
- 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?
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?
- 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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