14.4 Mechanisms of other antimicrobial drugs  (Page 2/15)

The polyenes are a class of antifungal agents naturally produced by certain actinomycete soil bacteria and are structurally related to macrolides . These large, lipophilic molecules bind to ergosterol in fungal cytoplasmic membranes, thus creating pores. Common examples include nystatin and amphotericin B . Nystatin is typically used as a topical treatment for yeast infections of the skin, mouth, and vagina, but may also be used for intestinal fungal infections. The drug amphotericin B is used for systemic fungal infections like aspergillosis , cryptococcal meningitis , histoplasmosis , blastomycosis , and candidiasis . Amphotericin B was the only antifungal drug available for several decades, but its use is associated with some serious side effects, including nephrotoxicity (kidney toxicity).

Amphotericin B is often used in combination with flucytosine , a fluorinated pyrimidine analog that is converted by a fungal-specific enzyme into a toxic product that interferes with both DNA replication and protein synthesis in fungi. Flucytosine is also associated with hepatotoxicity (liver toxicity) and bone marrow depression.

Beyond targeting ergosterol in fungal cell membranes, there are a few antifungal drugs that target other fungal structures ( [link] ). The echinocandins , including caspofungin, are a group of naturally produced antifungal compounds that block the synthesis of β(1→3) glucan found in fungal cell walls but not found in human cells. This drug class has the nickname “penicillin for fungi.” Caspofungin is used for the treatment of aspergillosis as well as systemic yeast infections.

Although chitin is only a minor constituent of fungal cell walls, it is also absent in human cells, making it a selective target. The polyoxins and nikkomycins are naturally produced antifungals that target chitin synthesis. Polyoxins are used to control fungi for agricultural purposes, and nikkomycin Z is currently under development for use in humans to treat yeast infections and Valley fever ( coccidioidomycosis ), a fungal disease prevalent in the southwestern US. Centers for Disease Control and Prevention. “Valley Fever: Awareness Is Key.” http://www.cdc.gov/features/valleyfever/. Accessed June 1, 2016.

The naturally produced antifungal griseofulvin is thought to specifically disrupt fungal cell division by interfering with microtubules involved in spindle formation during mitosis. It was one of the first antifungals, but its use is associated with hepatotoxicity . It is typically administered orally to treat various types of dermatophytic skin infections when other topical antifungal treatments are ineffective.

There are a few drugs that act as antimetabolites against fungal processes. For example, atovaquone , a representative of the naphthoquinone drug class, is a semisynthetic antimetabolite for fungal and protozoal versions of a mitochondrial cytochrome important in electron transport. Structurally, it is an analog of coenzyme Q , with which it competes for electron binding. It is particularly useful for the treatment of Pneumocystis pneumonia caused by Pneumocystis jirovecii . The antibacterial sulfamethoxazole-trimethoprim combination also acts as an antimetabolite against P. jirovecii .