Antifungal Agents in Pharmacology

Fungi are a vast group of organisms that play a vital role in our environment. Only a tiny fraction of all fungi species are harmful to humans. Those fungi that do cause disease, however, are infamous for their role in conditions like candidiasis (yeast infection), athlete's foot, ringworm and jock itch. Designing drugs to treat fungal infections is a complex task, much of which is beyond the scope of this article; nonetheless, some basic ideas in antifungal pharmacology are described below.

Function

• An antimicrobial drug must have selective toxicity, meaning that it must be highly toxic to the fungus while harming the patient as little as possible. The therapeutic index is a quantitative measure of an agent's selective toxicity. It's calculated by dividing the lethal dose (the dose that would kill the patient) by the therapeutic dose (the minimum effective dose). Designing antifungal agents is more difficult in general than designing antibacterial agents because it's more difficult to achieve selective toxicity. Fungi, like human cells, are eukaryotic, meaning they have a nucleus and other internal structures. Since fungi share more similarities with human cells than do bacteria, it can be challenging to develop a drug that will massacre the fungi while leaving human cells to escape unscathed.

Effects

• Antifungal drugs work by exploiting differences between human cells and fungi; one such difference involves sterols. Sterols are fatty compounds that play an important role in the cell membranes of fungi, plants and animals. A sterol called ergosterol is common in fungal cell membranes but absent in human cell membranes, which use cholesterol instead. Consequently, ergosterol is a target for multiple antifungal drugs. A few antibiotics can also kill fungal pathogens; two examples are polyoxin D and nikkomycin. These drugs work by attacking the process the fungi use to make chitin, a compound that forms the fungal cell wall; human cells don't manufacture or secrete chitin, so it's a potential target for antifungal drugs.

Types

• Antifungal drugs are divided into different classes by their chemical structure and the way they work. There are polyene antibiotics like nystatin and amphotericin B, both of which bind to ergosterol in fungal cell membranes, disrupting the cell membrane in ways that kill the fungus. Imidazoles like clotrimazole disrupt the synthesis of ergosterol so that the fungus can't produce the ergosterol it needs for its membrane. Flucytosine is a type of drug called a pyrimidine analogue; it's converted into a compound called 5-fluorouracil (5-FU) inside the fungus. 5-FU is similar in structure to one of the bases cells use to make RNA, so the clueless fungus incorporates the 5-FU when it's making RNA--and dies the death it so richly deserves.

Considerations

• Some antifungal agents are topical drugs that are applied to the site of an infection. Others are designed to be administered orally. When developing the latter kind of drug, researchers must bear in mind a variety of considerations that don't necessarily apply to a topical agent. Pharmacologists studying a drug candidate will want to know how well it's absorbed, how it's distributed through the body, how the body metabolizes it, and how it's excreted or eliminated from the body.

Warning

• Just like bacteria, fungal pathogens can develop drug resistance. Overuse of antifungal agents or discontinuing treatment before an infection is fully eliminated make it more likely the fungi will lose their susceptibility. Cases of drug-resistant Candida albicans, the culprit responsible for yeast infections, have become more common in recent years.