Lanosterol 14α-demethylase inhibitors

Lanosterol 14α-demethylase inhibitors are a class of antifungal drugs that work by inhibiting the enzyme lanosterol 14α-demethylase. This enzyme is crucial in the biosynthesis of ergosterol, a key component of the fungal cell membrane. By inhibiting this enzyme, these drugs disrupt the production of ergosterol, leading to increased membrane permeability and ultimately the death of the fungal cell. This mechanism of action makes lanosterol 14α-demethylase inhibitors effective in the treatment of various fungal infections.

Mechanism of Action

Lanosterol 14α-demethylase, encoded by the ERG11 gene in fungi, catalyzes the demethylation of lanosterol, a critical step in the ergosterol biosynthetic pathway. Ergosterol is analogous to cholesterol in human cells and is vital for maintaining the integrity and fluidity of the fungal cell membrane. Inhibition of lanosterol 14α-demethylase by these drugs results in the accumulation of toxic methylated sterol intermediates and a depletion of ergosterol within the cell membrane. This leads to increased membrane rigidity, disrupted cell signaling, and eventual cell lysis.

Clinical Use

Lanosterol 14α-demethylase inhibitors are primarily used in the treatment of systemic and superficial fungal infections. These include infections caused by Candida species, such as candidiasis, and dermatophytes, responsible for conditions like tinea pedis (athlete's foot), tinea cruris (jock itch), and tinea corporis (ringworm). They are also effective against more serious systemic infections such as cryptococcosis, caused by Cryptococcus species, and aspergillosis, caused by Aspergillus species.

Examples

Several drugs fall under the category of lanosterol 14α-demethylase inhibitors, including:

• Fluconazole - commonly used for the treatment of candidiasis and cryptococcal meningitis.
• Itraconazole - used for a variety of fungal infections, including aspergillosis and blastomycosis.
• Voriconazole - primarily used for the treatment of invasive aspergillosis.
• Posaconazole - used for the prophylaxis and treatment of certain fungal infections in immunocompromised patients.
• Ketoconazole - although less commonly used today due to its side effect profile, it was one of the first developed drugs in this class.

Side Effects

While lanosterol 14α-demethylase inhibitors are generally well-tolerated, they can cause side effects in some patients. Common adverse effects include gastrointestinal disturbances, liver enzyme elevations, and allergic reactions. Due to the potential for liver toxicity, monitoring of liver function tests is recommended during treatment with these drugs. Additionally, some drugs in this class can interact with a wide range of other medications, necessitating careful consideration of drug interactions.

Resistance

Resistance to lanosterol 14α-demethylase inhibitors can occur through various mechanisms, including mutations in the ERG11 gene, overexpression of efflux pumps that remove the drug from the cell, and alterations in the drug target that reduce drug binding. The emergence of resistance is a growing concern, particularly in immunocompromised patients and those with chronic infections, underscoring the need for judicious use of these medications.