6.9 The fungal wall as a clinical target

We will deal with therapeutic antifungal agents and their targets in detail in Chapter 18, but we can’t end a discussion of hyphal cell walls without mentioning the obvious point that synthesis and assembly of the fungal cell wall is an attractive target for antifungal chemotherapy. Antifungals that target chitin synthesis are of limited use at the moment even though the importance of chitin in the structure of the fungal wall would seem to make it an excellent target. Currently, the chitin synthesis inhibitors available are the naturally occurring nikkomycins and polyoxins, and their synthetic derivatives. These are analogues of the chitin synthase substrate, UDP-N-acetylglucosamine, and act as competitive inhibitors of chitin synthase. They can be effective when used in conjunction with other antifungal agents, but tend to be ineffective alone because limited uptake of the inhibitors (Bowman & Free, 2006).

The only aspect of wall synthesis that is effectively targeted by commercially available antifungal agents currently is the β1,3-glucan synthase, which is inhibited by the echinocandins. These non-competitive inhibitors of the glucan synthase are known to bind to the glucan synthase catalytic subunit. Echinocandins cause fungal cells to swell and the walls lyse at places of active cell wall synthesis.

Most pharmaceuticals currently in use for treatment of mycoses target aspects of fungal biology other than the cell walls. The most commonly used antifungals are azoles and polyene antibiotics that target ergosterol in the fungal plasma membrane. However, the structure of the cell wall is unique to the fungi and there are many steps controlled by enzymes that lack homologues in the human genome and are therefore good candidates as therapeutics: aside from chitin and glucan synthases and enzymes involved in cross linking wall components, there are the mannosyltransferases and glycosyltransferases in the Golgi apparatus, and the steps involved in attaching GPI anchors to cell wall proteins (Bowman & Free, 2006). These are the targets for future research.

Updated December 17, 2016