Treatment of an antifungal disease is quite difficult than a bacterial infection. The reason is quite clear that most of the eukaryotic fungal cells have a lot in common with human cells, so antifungal drugs can also damage the host body cells.

Also, some fungi have detoxification properties that can modify antifungal drugs and as a result, the effectiveness of these drugs will be reduced.

Nevertheless, there are several antifungal drugs that may be useful in treating fungal infections. These drugs are acted by extracting or preventing the synthesis of fungal membrane sterol without harming the mammalian cell, because of the fungal cell membranes have a unique sterol, called ergosterol, which replaces cholesterol found in mammalian cell membranes. Similarly, because fungal cell walls contain chitin, the enzyme chitin synthase is the target for antifungals such as polyoxin D and nikkomycin.

1. Polyenes Antifungal Drug

Polyenes Antibiotics also known as Polyene antimycotics. They are derived from some species of Streptomyces bacteria. Chemically, They composed of a large ring (cyclic ester ring). One side of this ring has multiple conjugated carbon-carbon double bonds (hence polyene), and on the other side of ring has multiple hydroxyl groups.

Example of Polyene: Natamycin, Nystatin, Amphotericin B, etc.

Mode of action of Different Polyenes Antibiotics

There are present different types of  Polyenes such as;

A. Natamycin 

• • Natamycin is an antifungal antibiotic that is derived from Streptomyces natalensis or S. chattanoogensis.
  • Natamycin mainly used to treat fungal infections of the eye.
  • Natamycin has a high affinity for steroids.
  • This antibiotic prevents fungal growth by binding to sterols on cell membrane.

Mode of Action of Natamycin:

• • First of all, Natamycin binds to ergosterol in the fungal plasma membrane.
  • Then it prevent ergosterol-dependent fusion of vacuoles.
  • As well as it also prevents membrane fusion and fission.
  • As a result, it causes death of fungal cells.

B. Nystatin

• • It is a type of channel-forming ionophore.
  • Nystatin has a broad-spectrum fungicidal and fungistatic activity against a number of yeasts and fungi.(Candida species)
  • This antifungal drug is synthesis by Streptomyces noursei.
  • The efficacy of Nystatin is limited to the treatment or prevention of cutaneous, mucocutaneous, and gastrointestinal fungal infections.

Mode of Action of Nystatin

• • It inhibit or destroy the fungal cell with the formation of a membrane-spanning pore in the fungal plasma membrane.
  • It causes a change in membrane permeability and as a result, it helps in leakage of intracellular contents and the subsequent disruption of electrochemical gradients necessary for proper cell function.

C. Amphotericin B

• • Amphotericin B has a high affinity for Ergosterolot the fungal cytoplasmic membrane.
  • This drug exhibits a higher in vitro activity against many species of fungi.
  • Amphotericin B can inhibit or prevent different types of Fungal infections which are caused by mainly Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus.
  • There are two species which are often resistant to amphotericin B such as Pseudallescheria boydii and Fusarium sp.

Mode of Action of Amphotericin B:

• • The mode of action of Amphotericin B depends on the concentration obtained in body fluids and the susceptibility of the fungus.
  • This drug binds with the ergosterol in the cell membrane of susceptible fungi.
  • After binding to ergosterol it creates a transmembrane channel.
  • This results change in membrane permeability allowing leakage of intracellular components.

2. Azoles Antifungal Drug

Azoles is a type of Antifungal drug Which is predominantly used for the treatment of different antifungal infection.  This drug act by preventing the synthesis of ergosterol on fungal cell membranes.

From the chemical structure Azoles belong from a class of five-membered heterocyclic compounds which contain a nitrogen atom and at least one other non-carbon atom.

Mode of action of Azoles: 

• • At first, the drug will destabilize the fungal cytochrome p450 51 enzyme, which leads to cell lysis.
  • The disruption in production of ergosterol creates holes on membrane as a result essential constituents of the fungal cells started to leak out. This kills the fungi.

Example of Azoles: Imidazoles, Triazoles, Thiazoles, all of them act on fungal in same way.

3. Allylamines Antifungal Drug

A. Terbinafine

• • Terbinafine is known as Terbinafine hydrochloride (Lamisil).
  • Terbinafine is a synthetic allylamine antifungal agent.
  • Terbinafine is highly lipophilic in nature and it has a tendency to accumulate in skin, nails, and fatty tissues.
  • This drug acts by inhibiting the synthesis of ergosterol in fungal cell by inhibiting a fungal enzyme squalene monooxygenase or epoxidase, which helps in synthesis of fungal cell wall.

4. Echinocandins Antifungal Drug

A. Anidulafungin

• • Anidulafungin is a type of semi-synthetic lipopeptide antifungal drug which is synthesized from a fermentation product of Aspergillus nidulans.
  • Anidulafungin act by inhibiting an enzyme, glucan synthase which is present in the fungal cell and responsible for the formation of 1,3-β-D-glucan.
  • 1,3-β-D-glucan is an essential component of fungal cell wall, hence after inhibition of 1,3-β-D-glucan  synthesis, it leads to osmotic instability and causes cell death.
  • This drug don’t affect the mammalian cell.

B. Caspofungin

• • It is a type of antifungal drug used for treatment of  Aspergillus and Candida infection.
  • This drug act by inhibiting cell wall synthesis.
  • Caspofungin act against fungi by inhibiting the synthesis of beta-(1,3)-D-glucan, which is an essential component of the cell wall of Aspergillus species and Candida species.
  • This drug don’t affect the mammalian cell because they lack beta-(1,3)-D-glucan.

C. Micafungin

• • It is a type of semisynthetic lipopeptide, which is synthesized from the fermentation product of Coleophoma empetri.
  • It acts by inhibiting the synthesis of beta-1,3-D-glucan (an essential component of fungal cell wall) with the inhibition of enzyme beta-1,3-D-glucan synthase (helps in the synthesis of beta-1,3-D-glucan).

5.Griseofulvin Antifungal Drug

• Griseofulvin is a fungistatic, which is administrated through oral route during the treatment of tinea infections.
• This drug is recommended for the treatment of tinea corporis, tinea pedis, tinea cruris, tinea barbae, cradle cap or other conditions caused by Trichophyton or Microsporum fungi.

Mode of Action of Griseofulvin

• • The exact mechanism of dermatophytes inhibition is not clear, however it is thought that Griseofulvin acts by inhibiting fungal cell mitosis and nuclear acid synthesis.
  • It also binds with the alpha and beta-tubulin and interferes with the function of spindle and cytoplasmic microtubules.
  • Griseofulvin also binds with the keratin in human cells, and once the drug reaches to the fungal site of action, it binds to fungal microtubes, and as a result, it will alter the fungal process of mitosis.

6. Ciclopirox Antifungal Drug

• Ciclopirox is a synthetic, broad-spectrum antifungal agent.
• Ciclopirox also has antibacterial and anti-inflammatory properties.
• This drug is mainly used for the treatment of topical dermatologic treatment of superficial mycoses.
• Ciclopirox mainly acts by disrupting DNA repair, cell division signals, and structures (mitotic spindles) as well as some elements of intracellular transport.

Mode of Action of ciclopirox

• • Ciclopirox acts by the chelation of polyvalent metal cations (Fe3+ and Al3+). These cations inhibit different types of enzymes, including cytochromes, as a result, they disrupt cellular activities such as mitochondrial electron transport processes and energy production.
  • Ciclopirox also acts by modifying the plasma membrane of fungi, which is resulting in the disorganization of internal structures.
  • Ciclopirox also shows anti-inflammatory action by inhibition of 5-lipoxygenase and cyclooxygenase.

7. Flucytosine Antifungal Drug

• Flucytosine is an antimetabolite which is acts as an antifungal agent with the help of in vitro and in vivo activity against Candida and Cryptococcus.

Mode of Action of Flucytosine

• • Flucytosine act by competitive inhibition of purine base and pyrimidine bae uptake and also indirectly by intracellular metabolism to 5-fluorouracil.
  • Flucytosine also enters into the fungal cell with the helps of cytosine permease; After entering flucytosine started to metabolized 5-fluorouracil within fungal organisms. The 5-fluorouracil is started to incorporated into fungal RNA and inhibits the synthesis of both DNA and RNA. This results in an unbalanced growth and death of the fungal organism.
  • Flucytosine also acts by inhibitions of fungal thymidylate synthase.

8. Tolnaftate Antifungal Drug

• Tolnaftate is a synthetic over-the-counter anti-fungal agent.
• This drug is active against Epidermophyton, Microsporum, and Malassezia furfur.

Mode of Action of Tolnaftate:

• • The exact mechanism of this drug is unknown, but it is believed that it helps to prevent ergosterol biosynthesis by inhibiting squalene epoxidase.

Reference

• https://en.wikipedia.org/wiki/Sterol#Types
• https://journals.plos.org/plospathogens/article/figures?id=10.1371/journal.ppat.1007478
• https://en.wikipedia.org/wiki/Griseofulvin
• https://www.drugbank.ca/drugs/DB01188
• https://en.wikipedia.org/wiki/Antifungal
• https://www.drugbank.ca/drugs/DB01099