Mechanisms of action in antifungal drugs
Antifungal drugs are essential for treating infections caused by harmful fungi in the human body. These medications target unique components of fungal cells, such as chitin in their cell walls, which differ from those in bacteria, allowing for targeted action. Various classes of antifungal drugs exhibit distinct mechanisms of action. For instance, allylamines and benzylamines inhibit an enzyme involved in ergosterol production, leading to fungal cell death by reducing ergosterol levels and causing squalene accumulation. Azoles, another common class, work by inhibiting lanosterol demethylation, disrupting ergosterol synthesis and ultimately affecting cell membrane integrity and function. Polyenes act by binding to ergosterol, creating pores in the cell membrane that lead to cell lysis. Other antifungal agents, like echinocandins and flucytosine, employ different mechanisms that disrupt cell wall synthesis and RNA metabolism, respectively. Understanding these mechanisms is crucial for effective treatment, especially as fungal resistance to older antifungals becomes more prevalent, highlighting the importance of appropriate antifungal use in clinical settings.
Mechanisms of action in antifungal drugs
Definition
Antifungal drugs are used to prevent the growth and reproduction of fungi that are harmful to the human body. The components of fungal cell walls are different from those in bacterial cell walls and are composed primarily of chitin, a polysaccharide. The differences in cell-wall composition have enabled researchers to target antifungals to components and building blocks specific to fungal cells.
Allylamines and Benzylamines
Allylamines are inhibitors of squalene 2,3-epoxidase, the enzyme responsible for the conversion of squalene to squalene oxide. Squalene oxide is an intermediate and marks a beginning step in the production of ergosterol, one of the key fungal cell-wall components.
Inhibiting the conversion of squalene to squalene oxide results in two important downstream results, which lead to cell death. The two resulting consequences are a decrease in the amount of ergosterol available and, more critical, the increased concentration of squalene within the fungal cell. Examples of commercially available allylamines are naftine and terbinafine. They are often used for topical and nail fungal infections.
The mechanism of action of benzylamines is similar to that of allylamines. Benzylamines inhibit squalene epoxidase, leading to the same dual mechanism of fungal cell death seen with allylamines: a decrease in the amount of ergosterol and the accumulation of squalene. Butenafine, the only commercially available benzylamine, is an over-the-counter medication for topical fungal infections such as ringworm.
Azoles
Azole antifungals include imidazoles and triazoles. Azoles are some of the most commonly used antifungals. Some are available over-the-counter and others require a prescription. They are used for both topical and systemic infections.
Imidazoles contain two nitrogen atoms in the core azole ring, whereas triazoles contain three nitrogen atoms. However, their mechanisms of action do not differ substantially. Azoles are fungistatic, although they may be fungicidal at much higher than normal concentrations.
Azoles inhibit the lanosterol 14-alpha demethylase, the enzyme responsible for converting lanosterol to ergosterol, a key component of the fungal cell membrane. Decreasing the concentration of ergosterol results in increased permeability and rigidity and a decrease in replication and growth of the of the fungal cells. Examples of commercially available azoles include clotrimazole, econazole, fluconazole, itraconazole, ketoconazole, miconazole, oxiconazole, and voriconazole.
Polyenes
Polyenes bind irreversibly to ergosterol, a sterol component of the fungal cell-wall membrane. This interaction creates pores within the fungal cell membrane, facilitating the release of intracellular components and eventual fungal cell death. Examples of commercially available polyenes include nystatin and amphotericin B. Amphotericin B is generally reserved for intravenous use for systemic fungal infections, whereas nystatin can be used for either systemic or oral fungal infections.
Other Antifungals
Echinocandins are lipopeptides that exert fungicidal activity against some fungal species through noncompetitive inhibition of (1,3)beta-glucan synthase. This decreases the glucan, a cell-wall component specific to fungal cells, and decreases the amount of ergosterol and lanosterol. Commercially available echinocandins include caspofungin, micafungin, and anidulafungin.
Flucytosine is an antimetabolite that disrupts protein synthesis and disrupts ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and pyrimidine metabolism; it is used for severe fungal infections. After entering the fungal cell, flucytosine undergoes a series of deamination and phosphorylation reactions and is eventually incorporated into RNA. Ciclopirox olamine, the only commercially available hydroxypyridone, has a mechanism of action distinct from other antifungals. Ciclopirox creates a polyvalent cation through chelation reactions with trivalent cations. This large polyvalent cation disrupts enzyme function, electron transport, cellular uptake mechanisms, and energy production. Griseofulvin is a fungistatic compound with a mechanism of action not completely understood. It is thought to potentially bind to alpha and beta tubulin, leading to the disruption of mitosis and nucleic acid synthesis.
Ibrexafungerp, also known as Brexafemme, is an antifungal medication that acts via the inhibition of the enzyme glucan synthase. It is used orally for the treatment of vulvovaginal candidiasis, and was granted FDA approval on June 1, 2021.
Impact
Fungal infections can range from the relatively harmless tinea pedis (athlete’s foot) to more serious systemic fungal infections, such as histoplasmosis and aspergillosis, in immunocompromised persons. As with bacterial resistance to antibiotics, fungal resistance has developed against some commonly used, older antifungals. Understanding the mechanism and spectrum of action of antifungals can help guide the clinician to more targeted, successful therapy. The improper use of antifungals puts at risk the health of the infected person and, ultimately, the public.
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