Chitin Synthase Inhibitors

Chitin is synthesized on the cytoplasmic surface of the plasma membrane as a linear homopolymer of ß-(1,4)-linked-N-acetyl-d-glucosamine (GlcNAc) residues. It extrudes perpendicularly from the cell surface as microfibrils to crystallize outside the cell through extensive hydrogen bonding as a-chitin. Polymerization of GlcNAc is catalyzed by the membrane-bound enzyme chitin synthase (Wills et al., 2000; Hector, 1993). Absence of chitin from mammalian cells makes it a potential target for therapeutic use. The two structurally related groups of secondary fermentation metabolites that act as specific inhibitors of chitin synthase, nikkomycins, and polyoxins, bear strong resemblance to uridine diphosphate (UDP)-GlcNAc, a chitin precursor substrate (Figure 4.3). The antifungal activity of different chitin synthase inhibitors varies depending on their differential capacity to permeate the cell wall.

Nikkomycin (C20H25N5O10) is produced by Streptomyces tendae TU901; currently, 14 naturally derived nikkomycin (Bx, Bz, Cx, Cz, D, E, I, J, M, N, X, Z, Pseudo-J, and Pseudo-Z) variants are known (Wills et al., 2000). Nikkomycin has fungicidal activity against the dimorphic fungi C. immitis and B. dermatitidis; C. albicans, and C. neoformans are Nikkomycin resistant (Hector et al., 1990). MICs for Nikkomycins X and Z against C. immitis are 0.77 and 0.1 |ig/mL while that against B. dermatitidis are 8 and 30 |g/mL, respectively (Graybill et al., 1998b; Hector et al., 1990). Additive in vitro effects are attainable against filamentous fungi (Aspergillus) by combining nikkomycin Z with caspofungin (Ganesan et al., 2004; Stevens, 2000). Pairwise combinations of nikkomycin Z with caspofungin or micafungin result in synergistic activity against A. fumigatus (Ganesan et al., 2004).

Aureobasidins is an 18 member family with a common structure of 8 lipophilic amino acid residues and an a-hydroxy acid synthesized by Aureobasidium pullulans. Auroebasidins lyse target cells by altering chitin assembly and sphingoli-pid synthesis (Endo et al., 1997; Nagiec et al., 1997). Aureobasidins A, B, C, E, S2b, S3, and S4 are active against Candida spp. and C. neoformans with MICs of 0.053.12 |g/mL; the MICs for H. capsulatum and B. dermatitidis are <0.63 |ig/mL. Aureobasidin A is active against dematiceous fungi at <2.5 |g/mL but has little activity against Aspergillus spp. (Kurmoe et al., 1996). Synthetic aureobasidin A is highly fungicidal to Candida and C. neoformans with an MIC of 0.01-1.6 |g/mL (Kurmoe et al., 1996).

Antifungal compounds targeting protein synthesis: Both fungal and mammalian cells require two elongation factors (EF), EF1a and EF2, for polypeptide chain elongation. However, with the discovery of EF3, a new essential factor for protein synthesis unique to yeast cells, fungal translation has evolved as a desirable target. This 120-125 kDa protein is present in most fungi, including C. albicans and P. carinii to provide an ATPase activity specifically required by the 40S ribosomal subunit of yeast cells to translocate growing polypeptides (Kovalchuke & Chakraburtty, 1994). Sordarins, a new class of antifungals prepared from the fermentation broth of Sordaria araneosa, inhibit protein synthesis in pathogenic fungi. The primary targets for sordarins are EF2 and the large ribosomal subunit ho oh o- / hn oh nh2

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