Antifungals - or antifungals - are drugs used to treat infections caused by fungi, including yeasts and molds. These infections are called mycoses .
Introduction
However, this argument does not apply to immunocompromised individuals. In fact, the spread of AIDS and the use of powerful immunosuppressive drugs in the prevention of rejections in transplants and in cancer chemotherapy, have increased the incidence of potentially lethal fungal infections. Therefore, the need has arisen to develop increasingly effective and safe antifungal drugs.
The difficulty in developing antifungal drugs lies in the high selectivity they must have. In fact, the differences between fungal cells and mammalian cells are very few, since both are eukaryotic cells.
However, although minimal, there are some differences between these two types of cells:
- The presence of the cell wall in fungal cells, but not in those of mammal;
- The composition of cell membranes. In particular, the fungal cell membranes differ from those of mammal for the sterols present within them. Sterols are indispensable components of the cell membrane; ergosterol is present in fungal cells, while cholesterol is present in mammalian cells.
It is therefore clear why the cell wall and ergosterol constitute two of the main targets of antifungal therapy.
Classes of antifungal drugs
In summary, the targets for an antifungal therapy that is selective only for fungal cells are essentially two: the fungal cell wall and the ergosterol contained in the cell membrane.
Therefore, most antifungal drugs work by destroying or interfering with the synthesis of these two fundamental components for fungal cells.
The classes of antifungal drugs currently on the market will be briefly described below.
Antifungals that alter the cell membrane
From the chemical point of view, these antifungal drugs are polyenes, ie they are aliphatic hydrocarbons containing numerous carbon-carbon double bonds within their chemical structure.
These polyenes have a high affinity for sterol-containing cell membranes. More specifically, polyenes have a great affinity for ergosterol-containing membranes (such as fungal ones).
These drugs are able to fit inside the cell membrane and increase their permeability. This increase causes the cells to lose constituents that are essential to them (such as ions and small organic molecules) and - consequently - they die.
Nystatin, amphotericin B and natamycin belong to this class of drugs.
Ergosterol biosynthesis inhibitors
These drugs act by inhibiting one of the key enzymes of ergosterol synthesis, 14α-demethylase.
With the inhibition of this enzyme there is an accumulation of ergosterol precursors; this accumulation generates alterations in the permeability of the cell membrane and causes alterations in the functioning of membrane proteins, thus condemning the fungal cell to certain death.
The drugs that belong to this class are numerous; these include ketoconazole, itraconazole, terconazole, fluconazole, voriconazole and posaconazole .
Squalene epoxidase inhibitors
Squalene epoxidase is an enzyme involved in the synthesis process of ergosterol.
In particular, this enzyme converts squalene (a precursor of ergosterol) to squalene epoxide (another precursor of ergosterol) which - following other enzymatic reactions - is then transformed into ergosterol.
Inhibition of squalene epoxidase causes:
- A reduction of the total ergosterol content within the fungal cell membrane, this causes alterations in the permeability of the membrane itself and malfunctions of the membrane proteins involved in nutrient transport and in the regulation of cellular pH;
- An accumulation of squalene inside the fungal cell which - when it reaches too high quantities - becomes toxic to the cell itself.
All this leads to the death of the fungal cell.
This class of antifungals includes naftifina, terbinafine, tolnaftate and amorolfine .
Biosynthesis inhibitors of the fungal cell wall
These antifungal agents inhibit one of the enzymes involved in the synthesis of the fungal cell wall, β-1, 3-glucan synthase. This enzyme is responsible for the synthesis of β-glucan, which is a fundamental element of the cell wall. A decrease in the amount of β-glucan inside the wall causes it to weaken to cause lysis of the fungal cell.
Caspofungin, anidulafungin and micafungin belong to this class of drugs.
Antifungal drugs acting with other mechanisms
There are also antifungal drugs that do not interfere with the synthesis of the cell wall or membrane sterols, but act with different mechanisms.
Among these drugs, we find:
- Flucitosina : it is a powerful antifungal that has no cytotoxic activity (toxic for the cell) per se. Flucytosine, in fact, is a prodrug that is internalized in fungal cells and here it is metabolized to 5-fluorouracil (a cytotoxic agent) which - following further metabolism - is converted into 5-fluorodeoxyuridine, a metabolite capable of interfering with the protein synthesis. 5-fluorouracil is also used as such in anti-tumor chemotherapy.
- Griseofulvin : this drug is an antifungal antibiotic derived from a particular strain of the genus Penicillium . Griseofulvin is mainly used in the treatment of superficial mycoses. Once administered orally, griseofulvin is able to incorporate into keratin and prevent fungal growth. Furthermore, it appears that this drug may interfere with the synthesis of mycotic DNA.
- Ciclopirox : this drug is mainly used in the treatment of superficial fungal infections. The ciclopirox has a very particular mechanism of action, that is, it is able to chelate (that is to tie through particular types of bonds defined as "coordinative" or "coordination") polyvalent cations - such as, for example, Fe3 + - thus causing the inhibition of metal-dependent enzymes found within the fungal cell.
- Undecylenic acid : this antifungal is mainly used in infections caused by dermatophytes (the fungi responsible for infections of the skin, nails and hair). However, undecylenic acid is not able to kill the fungal cell, but it has a fungistatic action (ie it inhibits fungal proliferation) and performs its action interacting in a non-specific way with the components of the cell membrane.
