Fungal infections range from mild skin conditions to life-threatening systemic diseases, particularly in immunocompromised patients. Unlike bacteria, fungi are eukaryotic organisms, which makes antifungal therapy more challenging because their cells share many structural and metabolic similarities with human cells. As a result, antifungal drugs must selectively target unique fungal components such as ergosterol (a key membrane sterol) or cell wall polysaccharides.
In this article, we will explore the major classes of antifungal drugs, their mechanisms of action, and clinical applications.
1. Polyenes
Examples: Amphotericin B, Nystatin
Mechanism:
Polyenes bind to ergosterol in the fungal cell membrane, creating pores that increase membrane permeability and cause leakage of cellular contents.
Clinical Use:
- Amphotericin B: Broad-spectrum antifungal, used for severe systemic infections (e.g., cryptococcosis, mucormycosis, histoplasmosis).
- Nystatin: Topical/oral use for superficial infections (e.g., oral thrush, vaginal candidiasis).
Limitations: Nephrotoxicity (kidney damage) is a major concern with Amphotericin B.
2. Azoles
Examples: Ketoconazole, Fluconazole, Itraconazole, Voriconazole, Posaconazole
Mechanism:
Azoles inhibit the enzyme lanosterol 14-α-demethylase, blocking the conversion of lanosterol to ergosterol. This disrupts fungal cell membrane synthesis.
Clinical Use:
- Fluconazole: Effective against Candida infections and cryptococcal meningitis.
- Itraconazole: Used in histoplasmosis, blastomycosis, and onychomycosis.
- Voriconazole: First-line for invasive aspergillosis.
- Posaconazole: Effective for mucormycosis and prophylaxis in immunocompromised patients.
Limitations: Hepatotoxicity and drug–drug interactions due to CYP450 inhibition.
3. Echinocandins
Examples: Caspofungin, Micafungin, Anidulafungin
Mechanism:
Echinocandins inhibit β-(1,3)-D-glucan synthase, an enzyme necessary for fungal cell wall synthesis. Without a functional cell wall, fungal cells undergo lysis.
Clinical Use:
- Effective against Candida (including resistant strains) and Aspergillus.
- Often used in invasive candidiasis and esophageal candidiasis.
Limitations: Limited oral bioavailability (administered IV only).
4. Allylamines
Examples: Terbinafine, Naftifine
Mechanism:
Allylamines inhibit squalene epoxidase, an enzyme required for ergosterol synthesis. This causes toxic accumulation of squalene and disrupts membrane integrity.
Clinical Use:
- Terbinafine: Commonly used for dermatophytic infections (tinea pedis, tinea corporis, onychomycosis).
Limitations: Hepatotoxicity and gastrointestinal side effects.
5. Pyrimidine Analogs
Example: Flucytosine (5-FC)
Mechanism:
Flucytosine is converted by fungal cytosine deaminase into 5-fluorouracil (5-FU), which inhibits DNA and RNA synthesis.
Clinical Use:
- Used in combination with Amphotericin B for cryptococcal meningitis.
- Sometimes used with azoles for synergistic effect.
Limitations: Resistance develops rapidly if used as monotherapy; bone marrow suppression and gastrointestinal toxicity are notable adverse effects.
6. Griseofulvin
Mechanism:
Griseofulvin interferes with microtubule function and disrupts mitotic spindle formation, inhibiting fungal cell division.
Clinical Use:
- Effective against dermatophyte infections (skin, hair, nails).
- Taken orally for tinea infections resistant to topical therapy.
Limitations: Slow onset of action; requires weeks to months of treatment.
7. Other/Novel Agents
- Ciclopirox: Topical antifungal used in nail and skin infections; disrupts fungal enzymes.
- Tavaborole: Inhibits leucyl-tRNA synthetase, blocking protein synthesis; used for onychomycosis.
- Ibrexafungerp: A newer oral glucan synthase inhibitor with similar action to echinocandins.
Summary Table of Antifungal Classes
| Drug Class | Target | Examples | Clinical Use | Key Limitation |
|---|---|---|---|---|
| Polyenes | Membrane (ergosterol binding) | Amphotericin B, Nystatin | Systemic & superficial mycoses | Nephrotoxicity |
| Azoles | Ergosterol synthesis (CYP450) | Fluconazole, Voriconazole | Candida, Aspergillus, endemic mycoses | Drug interactions |
| Echinocandins | Cell wall (β-glucan synthase) | Caspofungin, Micafungin | Invasive candidiasis, aspergillosis | IV only |
| Allylamines | Ergosterol synthesis (squalene epoxidase) | Terbinafine | Dermatophytes, onychomycosis | Hepatotoxicity |
| Pyrimidine analog | DNA/RNA synthesis | Flucytosine | Cryptococcal meningitis (with Amph B) | Rapid resistance |
| Griseofulvin | Microtubule inhibition | Griseofulvin | Dermatophytes | Long treatment |
Conclusion
Antifungal therapy remains a cornerstone in the management of superficial and systemic fungal infections. Each class of antifungal drugs targets a unique aspect of fungal physiology, from ergosterol and glucan synthesis to nucleic acid production. However, limitations such as toxicity, resistance, and drug interactions underscore the need for careful selection based on infection type and patient condition. With emerging antifungals and novel targets, the future of antifungal therapy looks promising in the ongoing battle against fungal diseases.