Antifungal Drugs: Videos & Practice Problems

Antifungal drugs target fungal cell membranes and walls by exploiting differences like ergosterol in membranes versus cholesterol in humans. Azoles and allylamines inhibit ergosterol synthesis, while polyenes disrupt existing ergosterol. Echinocandins inhibit beta glucan synthesis, destabilizing fungal cell walls. Flucytosine, a nucleic acid analog, disrupts fungal DNA/RNA synthesis after fungal-specific conversion. Griseofulvin inhibits microtubule assembly, preventing fungal cell division, concentrating in keratin-rich tissues like skin, hair, and nails. These mechanisms ensure selective toxicity against fungi, crucial for treating infections such as cutaneous mycoses and systemic mycoses effectively.

Antifungal Drugs

Antifungal drugs are categorized based on their mechanisms of action, targeting unique features of fungal cells to achieve selective toxicity. Since fungi are eukaryotes like humans, developing antifungal agents is challenging because both share many cellular structures. However, differences in the fungal cell membrane and cell wall provide effective targets for treatment.

The fungal cell membrane contains sterols that stabilize its structure. Unlike human cells, which use cholesterol, fungi incorporate ergosterol into their membranes. This difference allows antifungal drugs to selectively target ergosterol. One approach is to inhibit ergosterol synthesis using azole drugs such as clotrimazole (commonly used for skin infections like athlete’s foot) and miconazole (used for vaginal yeast infections). Allylamines, like terbinafine (brand name Lamisil), also inhibit ergosterol production, effectively treating skin fungal infections.

Another strategy involves directly disrupting ergosterol in the fungal membrane. Polyene drugs, including nystatin and amphotericin B, bind to ergosterol, creating pores that compromise membrane integrity. Amphotericin B is typically reserved for severe systemic infections and administered intravenously due to its potency and toxicity profile.

Fungal cell walls differ significantly from bacterial cell walls; they lack peptidoglycan and instead contain beta-glucan, a polysaccharide essential for cell wall strength. Echinocandins inhibit beta-glucan synthesis, weakening the fungal cell wall and causing cell lysis. These drugs are also used intravenously for serious infections, exploiting the unique fungal cell wall component to minimize harm to human cells.

Inhibiting nucleic acid synthesis is another antifungal mechanism. Flucytosine, a cytosine analog, interferes with fungal DNA and RNA synthesis. It is selectively toxic because fungi possess an enzyme that converts flucytosine into its active form, which disrupts nucleic acid production. Humans lack this enzyme, so flucytosine remains inactive in our cells. This drug is often combined with amphotericin B to enhance efficacy against severe fungal infections.

Lastly, some antifungal drugs disrupt fungal cell division by inhibiting microtubule assembly, essential for mitosis. Griseofulvin is an oral antifungal that binds to fungal microtubules more effectively than human ones, reducing toxicity. It accumulates in keratin-rich tissues such as skin, hair, and nails, where fungal infections commonly occur. This selective accumulation allows griseofulvin to treat infections like onychomycosis (fungal nail infections) by concentrating in non-living keratinized tissues, minimizing harm to living human cells.

Understanding these mechanisms highlights the importance of targeting fungal-specific structures like ergosterol and beta-glucan, as well as exploiting unique fungal enzymes and tissue tropisms. This knowledge is crucial for selecting appropriate antifungal therapies and managing fungal infections effectively.

Antifungal Drugs Example 1

Antifungal medications often target specific components of fungal cells to effectively treat infections. One key target is the sterols in fungal cell membranes, which are essential for membrane stability. Unlike animal cells that contain cholesterol, fungal cell membranes contain ergosterol. Therefore, antifungals that disrupt cell membranes specifically target ergosterol, not cholesterol.

Another important class of antifungals is echinocandins, which inhibit the synthesis of beta-glucan, a critical polysaccharide component of the fungal cell wall. By disrupting beta-glucan production, echinocandins weaken the cell wall, leading to a loss of rigidity and potential cell lysis. This mechanism targets the cell wall rather than the cell membrane.

When considering antifungals that inhibit nucleic acid synthesis, flucytosine is a prime example. Flucytosine is converted within fungal cells into a cytosine analog, which interferes with DNA and RNA synthesis, thereby halting fungal replication. This contrasts with drugs like miconazole, which primarily disrupt ergosterol synthesis in the cell membrane.

Many over-the-counter (OTC) antifungal medications, such as azoles and allylamines, primarily affect the cell membrane of fungi. These drugs are commonly used to treat superficial fungal infections like athlete’s foot, vaginal yeast infections, and candidiasis by targeting ergosterol synthesis and compromising membrane integrity.

Which of the following drugs target ergosterols in fungal cell membranes?
I) Nystatin
II) Miconazole
III) Flucytosine
IV) Griseofulvin

• A. I & II.
• B. II & III.
• C. I, II, & III.
• D. I & IV.

Answer: (A)

Which of the following correctly matches the drug with what the drugs inhibits?

• A. Echinocandins: beta-glucan synthesis.
• B. Azoles: DNA and RNA polymerase.
• C. Griseofulvin: peptidoglycan synthesis.
• D. Flucytosine: ergosterol synthesis.

Answer: (A)

Here’s what students ask on this topic:

What are the main categories of antifungal drugs and how do they work?

Antifungal drugs are mainly categorized based on their mechanism of action targeting fungal cells. The four major categories include: 1) Drugs that disrupt the fungal cell membrane by targeting ergosterol, such as azoles and allylamines which inhibit ergosterol synthesis, and polyenes like amphotericin B and nystatin that bind directly to ergosterol to disrupt membrane integrity. 2) Echinocandins, which inhibit beta glucan synthesis, weakening the fungal cell wall and causing cell lysis. 3) Drugs that inhibit nucleic acid synthesis, like flucytosine, a cytosine analog converted by fungal enzymes to disrupt DNA and RNA synthesis. 4) Drugs that inhibit fungal cell division by disrupting microtubule assembly, such as griseofulvin, which concentrates in keratin-rich tissues to treat skin, hair, and nail infections. These mechanisms exploit differences between fungal and human cells to achieve selective toxicity.

How do azole antifungal drugs inhibit fungal growth?

Azole antifungal drugs inhibit fungal growth by targeting the synthesis of ergosterol, a key sterol in fungal cell membranes. Ergosterol stabilizes the membrane structure, similar to cholesterol in human cells. Azoles inhibit the enzyme lanosterol 14α-demethylase, which is essential for converting lanosterol to ergosterol. By blocking this step, azoles reduce ergosterol production, leading to defective cell membranes that impair fungal cell function and growth. Common azoles include clotrimazole and miconazole, often used to treat skin and vaginal yeast infections. This selective inhibition exploits the difference between fungal ergosterol and human cholesterol, allowing effective antifungal therapy with minimal harm to human cells.

What is the role of echinocandins in antifungal therapy?

Echinocandins are antifungal drugs that target the fungal cell wall by inhibiting the synthesis of beta glucan, a critical polysaccharide component of the fungal cell wall. Unlike human cells, fungi have cell walls containing beta glucan, making this an excellent target for selective toxicity. By blocking beta glucan synthase, echinocandins weaken the cell wall, leading to instability and eventual cell lysis. These drugs are typically used intravenously for severe fungal infections. Examples include caspofungin and micafungin. Because human cells lack beta glucan, echinocandins have a high degree of selectivity and are effective in treating systemic mycoses with relatively low toxicity.

How does flucytosine selectively inhibit fungal nucleic acid synthesis?

Flucytosine is an antifungal drug that selectively inhibits fungal nucleic acid synthesis by acting as a prodrug. It is structurally similar to cytosine but is not itself a cytosine analog. Once inside fungal cells, flucytosine is converted by a fungal-specific enzyme into 5-fluorouracil, a cytosine analog. This metabolite is incorporated into fungal RNA and DNA, disrupting their synthesis and function, which inhibits fungal growth. Human cells lack the enzyme to convert flucytosine, so the drug remains inactive in human tissues, providing selective toxicity. Flucytosine is often used in combination with amphotericin B for serious systemic fungal infections.

Why is griseofulvin effective against fungal infections of skin, hair, and nails?

Griseofulvin is effective against fungal infections of the skin, hair, and nails because it inhibits fungal cell division by disrupting microtubule assembly. It binds to fungal microtubules more efficiently than human ones, impairing mitosis and fungal reproduction. Importantly, griseofulvin binds to keratin, the protein that makes up hair, nails, and the outer skin layer. These keratin-rich tissues are composed of dead cells, allowing griseofulvin to accumulate at high concentrations without harming living human cells. This targeted accumulation makes it particularly useful for treating dermatophytic infections like athlete's foot and nail fungus. The drug is administered orally and gradually concentrates in these tissues to exert its antifungal effects.

How do polyene antifungal drugs disrupt fungal cell membranes?

Polyene antifungal drugs, such as amphotericin B and nystatin, disrupt fungal cell membranes by directly binding to ergosterol, the primary sterol in fungal membranes. This binding creates pores or channels in the membrane, increasing its permeability. As a result, essential ions and molecules leak out of the fungal cell, leading to cell death. Because human cell membranes contain cholesterol instead of ergosterol, polyenes selectively target fungi. Amphotericin B is often used intravenously for severe systemic infections, while nystatin is commonly used topically for mucosal and skin infections. Despite their effectiveness, polyenes can have some toxicity due to partial binding to human cholesterol.