Antifungal Action Mechanism of of Azoles, Caspofungin and Terbinafine.pptx

1. Presentation
on
Antifungal action mechanisms of Azoles,
Caspofungin and Terbinafine as well as their
restances
Submitted by-
Samad Muhammad Abdus
ID-AM202318003
School of Medicine
Jeju National University
For-
Kang Hee-Kyung
Professor
School of Medicine
Jeju National University

2. A pharmaceutical fungicide or fungistatic called an antifungal medicine, sometimes referred to as an antimycotic
medication, is used to treat and prevent mycosis, including athlete's foot, ringworm, candidiasis (thrush), and
dangerous systemic infections such cryptococcal meningitis.
Yeasts, molds, or a mix of both can grow as fungi. They procreate by producing tiny spores. Both soil and airborne
forms of these spores are possible.
Antifungals come in two varieties: local and systemic. Depending on the illness being treated, topical or vaginal
administration of local antifungals is typical. Oral or intravenous administration is used for systemic antifungals.

4. Some of the most widely used antifungals are azoles. Azoles are synthetic antifungals that have broad-
spectrum fungistatic efficacy against yeasts, fungi, and even types of candida.
There are two subcategories of azole antifungal medications are: imidazoles and triazoles.
Imidazoles can be used to treat a variety of fungi, for instance:
Clotrimazole: Candida infections of the skin, mouth, and genital area.
Ketoconaole: Blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and
paracoccidioidomycosis are all systemic fungal diseases that can be treated with ketoconazole.
Miconazole: infections of the skin, nails, and vagina.
Triazoles are used to treat a variety of fungi, for instance:
Fluconazole: Used to treat candida and cryptococcus-related fungal infections.
Isavuconazole: Therapy for invasive aspergillosis and mucormycosis infections with isavuconazole.
Itraconazole: different superficial mycoses, aspergillosis, histoplasmosis, candidiasis, and blastomycosis.
Posaconazole: Treats candida and aspergillosis-related invasive fungal infections.
Voriconazole: Aspergillosis and candida:

5. All azoles contain a 5-membered, nitrogen-containing azole ring.
Imidazoles have 2 nitrogen atoms in the azole ring.
Triazoles have 3 nitrogen atoms in the azole ring.
Itraconazole
Fluconazole Ketoconazole
Voliconazole

6. Azoles damage the fungal cell membrane by suppressing the synthesis of ergosterol.
• A crucial element of fungal cell membranes is ergosterol (the equivalent to cholesterol in human cell
membranes)
• Lanosterol 14-demethylase, a fungus-derived CYP450 enzyme that transforms lanosterol to ergosterol.
Compared to human enzymes, azoles have a greater affinity for fungal enzymes.
• In comparison to imidazoles, triazoles have a higher selective affinity for fungal enzymes.
• Azoles prevent the formation of ergosterol by inhibiting lanosterol 14-demethylase.
• Without new ergosterol production: Fungi are unable to maintain the cell membrane or create new
membranes. ↑ Fungal cell membrane permeability → cell lysis
• Azoles are typically considered to be as being fungistatic.

8. Due to their fungistatic rather than fungicidal properties, azoles can cause the development of resistance, which
is a significant clinical issue in antifungal treatment.
The major ways that fungi develop resistance to azoles include-
1) Mutation of the drug’s target site → ↓ drug affinity for lanosterol 14-α-demethylase → ↓ inhibition
2) ↑ Efflux pumps → less drug within the fungal cell
3) Reduced uptake of the drug → less drug within the fungal cell
4) Target enzyme is overproduced.

9. James Balkovec, Regina Black, and Frances A. Bouffard developed the lipopeptide antifungal medication
capsofungin (INN) for Merck & Co., Inc. It belongs to the novel class of antifungal medicines known as
echinocandins, which has wide antifungal action against all Candida species.
The newest subclass of antifungal drugs is echinocandins. Three echinocandins are—
1) anidulafungin,
2) caspofungin, and
3) micafungin — have currently received clinical use authorization for a variety of applications.
All three medications in this family have been shown to be extremely successful or superior in well-defined
clinical contexts, such as invasive Candida infections, Candida oesophagitis, and candidaemia, when compared
to treatment with either fluconazole or Amphotericin B.
Caspofungin:

10. Mechanism of action of Caspofungin:
It functions by inhibiting the enzyme (13)-D-glucan synthase, which disrupts the consistency of the fungal cell
wall. The United States Food and Drug Administration initially authorized capofungin as a fungal (13)-D-glucan
production inhibitor.

11. Mechanism of action of Caspofungin (cont.):
Caspofungin blocks the synthesis of β(1,3)-D-glucan of the fungal cell wall, by non-competitive inhibition
of the enzyme β(1,3)-D-glucan synthase. β(1,3)-D-Glucan is an essential component of the cell wall of
numerous fungal species. The chains of β(1,3)-D-glucan form a solid three-dimensional matrix, which
gives the cell wall its shape and mechanical strength.
Inhibition of the synthesis of β(1,3)-D-glucan produces a double effect, both fungistatic and fungicidal. The
fungistatic effect results from blockade of the cell wall synthesis, reducing fungal growth. The fungicidal
effect results from a change in the integrity of the cell wall, which loses its mechanical strength and
becomes unable to resist the intracellular osmotic pressure, leading ultimately to destruction of the fungal
cell. This mechanism of action differs from that of other antifungal families, which act on the cell
membrane (polyenes, azoles or terbinafine), or inhibit DNA and protein synthesis (5-fluorocytosine).

12. Resistance mechanism of Caspofungin:

13. Resistance mechanism of Caspofungin (cont.):
The incidence of resistance to echinocandins is rare, but some case reports have illustrated the potential
for resistance development. Most often, echinocandin resistance is covered by mutations of the FKS
gene. Particularly, it was shown that FKS1 mutations were linked to a significant reduction in echinocandin
sensitivity. These alterations are thought to cause cross-resistance to all of the drugs in the class.
As a result of these mutations, the target enzyme glucan synthase experiences amino acid alterations that
change the medication's preferred binding site, resulting in drug resistance and clinical failures.
The existence of drug efflux pumps in the fungal cell wall is the second unique mechanism that can
provide resistance to echinocandins. The cdr2p gene, which is also known to play a role in fluconazole
resistance in C. albicans, was linked to a rise in caspofungin MICs.
Resistance to echinocandins is mostly observed in Candida spp.

14. Terbinafine:
Terbinafine is an allylamine antifungal medication. Terbinafine is a first-choice treatment option for
fingernail and toenail fungus.
Terbinafine is active in vitro against a wide range of pathogenic fungi, including dermatophytes, molds,
dimorphic fungi, Cr. neoformans and some but not all Candida and Aspergillus spp.
It's used to treat skin infections caused by a fungus (yeast), including:
• athlete's foot
• fungal nail infections
• ringworm
• jock itch (sometimes called dhobie itch), an infection in the groin area
• pityriasis versicolor – this causes small patches of scaly and discoloured skin, often on your back,
chest, upper arms, neck and stomach
• candidal skin infections

15. mechanism of action of Terbinafine:

16. Mechanism of action of Terbinafine (cont.):
By preventing the enzyme squalene monooxygenase, which is necessary for the production of sterol
in fungus, terbinafine has a fungicidal effect. By lowering ergosterol levels, this prevents the
formation of fungal sterols. Because ergosterol is one of the primary components of the fungal cell
membrane, fungal membranes cannot proliferate. Squalene builds up as well, weakening the cell
membrane. The drug's tendency to concentrate inside the nails makes it particularly efficient when
taken orally.
High intracellular squalene concentrations, which are thought to impair fungal membrane function
and cell wall formation, are strongly related to the cidal activity. The ergosterol deficit appears to be
the cause of the growth inhibition caused by terbinafine in the instance of Candida albicans.
This fungus' filamentous form is more prone to infection than its yeast form. In a variety of
pathogenic fungi, growth inhibition and ergosterol production are correlated, according to
measurements of the process using radiolabelled precursors.

17. Resistance mechanism of Terbinafine:
By preventing the enzyme squalene monooxygenase, which is necessary for the production of sterol
in fungus, terbinafine has a fungicidal effect. By lowering ergosterol levels, this prevents the
formation of fungal sterols. Because ergosterol is one of the primary components of the fungal cell
membrane, fungal membranes cannot proliferate. Squalene builds up as well, weakening the cell
membrane. The drug's tendency to concentrate inside the nails makes it particularly efficient when
taken orally.
High intracellular squalene concentrations, which are thought to impair fungal membrane function
and cell wall formation, are strongly related to the cidal activity. The ergosterol deficit appears to be
the cause of the growth inhibition caused by terbinafine in the instance of Candida albicans.
This fungus' filamentous form is more prone to infection than its yeast form. In a variety of
pathogenic fungi, growth inhibition and ergosterol production are correlated, according to
measurements of the process using radiolabelled precursors.

18. Resistance mechanism of Terbinafine (cont.):

19. Resistance mechanism of Terbinafine (cont.):
The figure presents the main resistance mechanisms observed in dermatophytes.
In (A), a reduced scheme of the biosynthesis of ergosterol is represented. In case of mutations in
squalene epoxydase gene, the terbinafine cannot inhibit the enzyme anymore, so there is no
reduction of ergosterol synthesis and no cell death anymore (no fungicidal effect), giving rise to
resistance.
In (B), the efflux mechanism by ABC transporters is mainly described for azoles resistance in
dermatophytes.

20. References:
1.https://www.frontiersin.org/articles/10.3389/fmicb.2017.00036/full
2.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821933/#:~:text=Resistance%20to%20trimethoprim%20i
s%20caused,)%20encoded%20by%20dfr%2Dgenes.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88922
/
3.https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-4856-8
4. https://www.sigmaaldrich.com/catalog/product/sigma/t8826?lang=en&region=US
5. https://www.chemicalbook.com/ChemicalProductProperty_CN_CB9767492.htm

21. Thank You