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Fungicides

Introduction

The principle being enunciated in this essay is that fungicides can be used to treat diseases caused by fungi. Diseases in humans and other mammals caused by fungi have only recently gained importance. The change in attitude has come about through an increase in tissue transplantation, and the virus HIV; both involve suppression of the immune system. The first approach to treatment of diseases caused by fungal pathogens is the use of fungicides.

However, considerable care in the use of fungicides is necessary. Fungi can evolve resistance to the fungicides. In general, resistant fungi either prevent entry, inactivate the molecule, prevent the molecule from docking with the target molecule, or remove the active compound from the cell before it causes damage.

Many classes of systemic antifungal compounds are currently in use. The action of three will be described and some possible problems with their continued use introduced.

Polyenes

Members of the Streptomyces produce polyene antifungal compounds. The compounds have a broad spectrum of activity, because the compounds are thought to act against the sterol ergosterol.

Ergosterol and related sterols are found in the plasma membrane of fungi, where they are important for maintaining structural integrity, membrane fluidity and the function of membrane-bound enzymes.

Polyenes intercalate into membranes forming a channel through which cell components, especially K ions, may pass. This destroys the proton gradient within the membrane.

Commonly used polyenes include LINK Nystatin and Amphotericin B. Nystatin and Amphotericin B have a greater affinity for ergosterol than cholesterol, thus they affect fungal membranes more than mammalian. However, especially with prolonged exposure, Nystatin and Amphotericin B may damage some tissues such as the kidney.

Fungal cells with a lower binding potential to polyenes are resistant to the compounds. The binding potential could be due to fewer ergosterol inclusions in the membranes, or a lower binding receptivity to the polyene.

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Azoles

Azoles are synthetic compounds, with two (imidazole) or three (triazole) nitrogens in the 5-member azole ring. They are one of a group of compounds known as Sterol Biosynthesis Inhibitors. Azoles act against ergosterol biosynthesis at the step lanosterol demethylase. The azoles bind to a haem preventing demethylation, and can also therefore be known as demethylation inhibitors. The result of binding is an increase in sterol precursors, with a consequent reduction in membrane integrity and altered structure. Cell multiplication is slowed severely and the altered cells are more susceptible to phagocytosis. Azoles also partially block cholesterol biosynthesis, and thus dosage must balance the action on all sterols in the target tissues.

Azoles in use include fluconazole, itraconazole and ketoconazole. Resistance to fluconazole has been found following long-term treatment of oral candidiasis in people with AIDS. The compounds have a similar mode of action, and resistance to Azoles appears to follow one of two mechanisms. The target enzyme may be modified, such that affinity is reduced, or the enzyme is over-expressed leading to a saturation of the fungicide, with unaltered ergosterol formation.

The second mechanism involves increased efflux of the azole. Efflux of azoles may be mediated by one of many enzymes in the plasmamembrane. Efflux of toxic compounds is a common and widespread mechanism resulting in protection of fungal cells. While some efflux pumps targeting azoles have been found, these are unlikely to be the only ones potentially able to reduce concentration of the fungicides within the cell.

As the target site of the fungicide is cytoplasmic, it is also possible that mechanisms either preventing entry or altering the functionality of the plasmamembrane may be found that effectively negate the action of azoles.

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Fluoropyrimidines

The fluoropyrimidine 5-FC has a limited spectrum of activity. 5 FC passes through the membrane via a permease. Inside the cell, 5 FC is converted into 5 fluorouracil (5 FU), ultimately being incorporated into RNA. The nucleoside causes disruption of protein synthesis in fungi. While 5 FC has a relatively low mammalian toxicity, 5 FU is a widely used anti-cancer agent. Thus use of 5 FC is limited.

Resistance to 5 FC has been reported. Uptake may be reduced if the permease is altered. Conversion to 5 FU may also be reduced if the enzymes involved with the various steps in conversion are modified. Efflux of the compound might also be predicted, as its action is within the cell.

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Conclusion

A limited number of compounds are used to reduce disease caused by fungi. While a range of compounds have been found that act against fungi, problems arise with their use in humans. Common biosynthetic pathways result in low levels of toxicity to the host. Resistance due to efflux of the fungal toxin or modification of the target enzyme are also common. The continued use of fungicides, especially in chronic conditions, will increase levels of resistance as has happened to bacterial pathogens.

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