Cell Wall Biosynthesis

Fungal cell wall is a crucial target for antifungal agents. Enzymes responsible for the biosynthesis of fungal cell wall include chitin and glucan synthases (Douglas et al. 1997; Georgopapadakou 1997). Antifungal agent echinocandins have been discovered as inhibitors of fungal cell wall biosynthesis (Denning 1997). They are noncompetitive inhibitors of b-1,3-glucan synthase, an enzyme complex in the cell wall of many pathogenic fungi. b-1,3-Glucan synthase is a fungal specific enzyme that polymerizes UDP-glucose into b-1,3-glucan polymers that comprise the major scaffolding of the fungal cell wall (Kang and Cabib1986). Echinocandins and its synthetic analog containing the fatty acid side chain, cilofungin, exhibited comparable fungicidal activity with a narrow antifungal spectrum (Fromtling 1994). Recently, marked improvements in antifungal activity against clinical pathogens have been achieved by synthetic variations made in the lipid side chains of echinocandins. LY30336 and caspofungin are the examples of recently developed echinocandin analogs (Espinel-Ingroff 1998), which are generally more active in vitro against a variety of yeast and filamentous fungi. They are licensed by Lilly and Merck, respectively, for clinical usage. Such a novel mechanism of action, antifungal potency and relatively broad-spectrum activity of echinocandins provide the possibility that the inhibitors of b-1,3-glucan synthase may be available for the development of biofungicides effective against fungal diseases (Pfaller et al. 1998).

Chitin, b-1,4-N-acetylglucosamine polymer, plays a major structural and strengthening role in fungal cell walls. Chitin is microfibrills consisting of hydrogen-bonded polysaccharide chains that may be covalently cross-linked to other polysaccharide, mainly glucan. It has been demonstrated that chitin synthase inhibitors and chitinase showed antifungal activity when applied to growing cells (Lorito et al. 1993). Nikkomycins are analogs of UDP-N-acetylglucosamine produced by Streptomyces spp. They have potent activity against chitin synthase by acting as specific competitive inhibitors (Hunter 1995). The potency of an inhibitor of chitinase synthase may depend on not only the isoform's relative effectiveness in building a cell wall, but also its affinity to a given enzyme. Recent research on chitin synthase revealed that the multiple chitin synthase genes of fungi have different sensitivities to the inhibitors (Munro and Gow 1995). Therefore, new antifungal compounds with higher activity and specificity to chitin synthase may be generated from diverse chemical pool of microbial metabolites.

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