14.4 Mechanisms of other antimicrobial drugs  (Page 24/15)

Learning objective

• Explain the differences between modes of action of drugs that target fungi, protozoa, helminths, and viruses

Because fungi, protozoa, and helminths are eukaryotic, their cells are very similar to human cells, making it more difficult to develop drugs with selective toxicity. Additionally, viruses replicate within human host cells, making it difficult to develop drugs that are selectively toxic to viruses or virus-infected cells. Despite these challenges, there are antimicrobial drugs that target fungi, protozoa, helminths, and viruses, and some even target more than one type of microbe. [link] , [link] , [link] , and [link] provide examples for antimicrobial drugs in these various classes.

Antifungal drugs

The most common mode of action for antifungal drugs is the disruption of the cell membrane. Antifungals take advantage of small differences between fungi and humans in the biochemical pathways that synthesize sterols. The sterols are important in maintaining proper membrane fluidity and, hence, proper function of the cell membrane. For most fungi, the predominant membrane sterol is ergosterol . Because human cell membranes use cholesterol , instead of ergosterol, antifungal drugs that target ergosterol synthesis are selectively toxic ( [link] ).

The imidazoles are synthetic fungicides that disrupt ergosterol biosynthesis; they are commonly used in medical applications and also in agriculture to keep seeds and harvested crops from molding. Examples include miconazole , ketoconazole , and clotrimazole , which are used to treat fungal skin infections such as ringworm , specifically tinea pedis ( athlete’s foot ), tinea cruris ( jock itch ), and tinea corporis . These infections are commonly caused by dermatophytes of the genera Trichophyton , Epidermophyton , and Microsporum . Miconazole is also used predominantly for the treatment of vaginal yeast infections caused by the fungus Candida , and ketoconazole is used for the treatment of tinea versicolor and dandruff , which both can be caused by the fungus Malassezia .

The triazole drugs, including fluconazole , also inhibit ergosterol biosynthesis. However, they can be administered orally or intravenously for the treatment of several types of systemic yeast infections, including oral thrush and cryptococcal meningitis , both of which are prevalent in patients with AIDS. The triazoles also exhibit more selective toxicity , compared with the imidazoles, and are associated with fewer side effects.

The allylamines , a structurally different class of synthetic antifungal drugs, inhibit an earlier step in ergosterol biosynthesis. The most commonly used allylamine is terbinafine (marketed under the brand name Lamisil ), which is used topically for the treatment of dermatophytic skin infections like athlete’s foot , ringworm , and jock itch . Oral treatment with terbinafine is also used for the treatment of fingernail and toenail fungus, but it can be associated with the rare side effect of hepatotoxicity .