Also known as mycoses Very large and diverse group of microorganisms Of major two types yeasts and molds Mycotic Infections Cutaneous Subcutaneous Superficial Systemic Can be lifethreatening ID: 909029
Download Presentation The PPT/PDF document "Antifungal agents Fungi" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Antifungal agents
Fungi
Also known as mycoses
Very large and diverse group of microorganisms
Of major two
types:
yeasts and molds.
Mycotic
Infections:
Cutaneous
Subcutaneous
Superficial
Systemic:
Can be life-threatening
Usually occur in
immunocompromised
host
Slide2Targets for Antifungal agents
Generally these targets should be different from mammalians.
Both human and fungi are eukaryotic, so not much difference could be found.
The most important difference is the presence of cell wall for fungi that is not found in humans.
Other targets are:
Inhibitors of DNA synthesis.
Disruption of mitotic spindle.
Interfere with metabolism.
The most exploited difference is the nature of sterols:
Important components of cell membrane for proper function of cell membrane enzymes and ion transporter proteins.
Slide3Targets for Antifungal agents
Mammalians contain cholesterol while fungi posses ergosterol.
The difference is in the side chain of ergosterol which is more flat compared to cholesterol;
A difference that is responsible for providing selectivity for the majority of antifungal agents.
Cholesterol
Ergosterol
Slide4Slide5Polyene membrane disrupters
Polyenes
: macrocyclic lactones with distinct hydrophilic and lipophilic regions.
Produced from Streptomyces species
Hydrophilic: alcohol, carboxylic acids, sugar.
Lipophilic: contain a pharmacophore of 4-7 conjugated double bonds.
The number of the double bonds correlate directly to activity and inversely to toxicity.
Amphotericin is 10X more active which can be taken systemically.
Mechanism of action: have affinity to ergosterols containing membranes, then inserted in the cell membrane, disrupts its function, leak of cell components.
Slide6Amphotericin
Slide7Polyene membrane disrupters
1- Nystatin
:
- A tetraene agent that used topically.
- No oral absorption, so used orally for mouth and GIT infections.
2- Amphotericin B
: - Heptaene derivative with low enough toxicity for I.V use, but still toxic drug used with caution.
- It does not cross BBB, so used intrathecally of brain fungal infections.
- The main side effect is nephrotoxicity, reduced by formulation change.
- Liposomal encapsulation was found to target infected tissues as the capillary size at the infected areas is larger, so release the drug specifically at that area.
Slide8Nystatin
Amphotericin nephrotoxicity
Slide9Ergosterol Biosynthesis inhibitors
A- Azoles
:
- The largest group of antifungal agents.
- Some used topically and others used systemically.
- some are orally bioavailable with broad spectrum properties.
- SAR:
- 5-membered ring with 2-3 Ns. - side chain attached to N. - At least has one aromatic ring.
- Mechanism of action: - Act by inhibiting
ergosterol synthesis by inhibiting CYP450 14-α-demethylase
, where the basic nitrogen N3 of the drug bind to
heme
iron of the enzyme blocking the active site.
Slide10Mechanism of action of Azoles
Slide11Ergosterol Biosynthesis inhibitors
- Inhibition will lead to accumulation of sterols with extra methyl group.
- This new sterol structure does not have the shape and physical properties of the normal ones, leading to permeability changes.
- Selectivity to mammalian C450 compared to the fungal one is 1:1000, and even, most of azoles considered mammalian C450 inhibitors which lead to serious drug-drug interactions in some cases.
- Systemic azoles are : Ketoconazole,
Itraconazole
,
Fluconazole
and voricanazole.
- Non-systemic azoles are : Clotrimazole, Oxiconazole
and
miconazole
.
Slide12Ergosterol Biosynthesis inhibitors
Ketoconazole
:
- Imidazole derivative, that is
orally active for systemic infections.
- Depends mainly on low stomach pH for absorption.
- Inhibit C450 causing serious drug-drug interactions.
- All its metabolites are inactive and mainly used topically.
Slide13Ergosterol Biosynthesis inhibitors
Ketoconazole
Metabolism:
- Deacylation.
- Aromatic hydroxylation.
Hydroxylation
Binds heme active site
Deacylation
Slide14Ergosterol Biosynthesis inhibitors
2- Itraconazole:
- Triazole derivative.
- Oral bioavailability depend on food and stomach pH.
- highly interfere with liver enzymes (serious drug drug interactions).
3-
Fluconazole
:
- Equal bioavailability, oral and I.V. - Could cross BBB (Why?).
- Weak inhibitor to some liver enzymes.
Slide15Ergosterol Biosynthesis inhibitors
B- Allylamines
:
- They have limited spectrum of activity which is only used for dermatophytes.
- Includes: Naftifine, Terbinafine, and Tolnaftate
- Mechanism of action: inhibit squalene epoxidase,
- leading to build up of squalene that it self is toxic compound.
- and also lead to reduction of sterol levels in cell membrane, leading to cell lysis.
- Mammalian squalene epoxidase is less sensitive to these drugs.
Slide16Slide17Ergosterol Biosynthesis inhibitors
-Terbinafine
:
- Topical and Oral.
- Active against many dermatophytes.
- Highly lipophilic. - Extensively metabolized.
Slide18Ergosterol Biosynthesis inhibitors
C- Morpholines
:
- Amorolfine
:
- The only drug of this class, used topically. - Act on
Δ14 reductase enzyme, and Δ
8, Δ7 isomerase enzymes.
- produce non-similar compounds with different physical properties, leading to cell leakage.
Slide19Miscellaneous mechanism of
actions
Flucytosine
:
Powerful agent for systemic infections.
Taken up by fungal cells and interferes with
DNA synthesis
Prodrug to produce 5-flurouracil.
Griseofulvin: Orally taken for superficial infections.
Not used topically.Bind to protein tubulin.
Interfere with cell division.
Slide20