O N

oh oh

Nikkomycin Z

Polyoxin B

oh hn o ch2oh ch2oh hh h2n^ ^o on hn hh on o h2n^ ^o

ohho oh oh ohho oh oh

UDP-N-acetylglucosamine

Figure 4.3 Chemical structures of nikkomycin Z, polyoxin B, and uridine diphosphate (UDP)-N- acetylglucosamine o ch2oh o o o o o stalk rpPO (Santos et al., 2004; Odds et al., 2003; Odds, 2001). EF2 promotes the displacement of tRNA from the A site to the P site and the movement of ribosome along the mRNA thread (Odds, 2001). A number of new sordarins, GM193663, GM-211676, GM-222712, GM-237354, and GR-135402 (Figure 4.4), are in different phases of preclinical or clinical evaluation. Sordarins are to C. albicans, C. glabrata, and C. tropicalis but inactive against C. krusei and C. parapsilosis (Herreros et al., 1998). While the activity of sordarins against C. neoformans, P. carinii, and H. capsulatum is well demonstrated, limited activity against A. fumig-atus has been suggested (Gargallo-Viola, 1999). Significant in vivo activity of sord-arins was reported in immunocompetent mouse models of disseminated and mucosal candidiasis (Martinez et al., 2000), histoplasmosis (Graybill et al., 1999), and coccidioidomycosis (Clemons & Stevens, 2000). Sordarins GM-193663, GM-211676, and GM-237354 were reported to be equivalent or superior to fluconazole in treating murine experimental systemic coccidioidomycosis (Graybill et al., 1999; Clemons & Stevens, 2000). Sordarins synergize with AMB, itraconazole, and voriconazole to yield better activity against Aspergillus spp. and S. apiospermum (Andriole, 1999).

Azasordarin exhibits superior activity against mucosal C. albicans and other Candida spp. infections (Herreros et al., 2001). GW-471558 (Figure 4.4) is active against C. albicans, C. glabrata, and C. tropicalis including some isolates insensitive to fluconazole but inactive agaisnt C. parapsilosis, C. krusei, C. guilliermondii, and C. lusitaniae (Cuenca-Estrella et al., 2001). GW-471552 and GW-471558 have significant therapeutic efficacy against vulvovaginal C. albicans infections (Martinez et al., 2001). R-35853, a sordarin derivative with a 1,4-oxazepane ring moiety (Figure 4.4), has good in vitro activity against fluconazole-susceptible C. albicans strains, C. glabrata, C. tropicalis, and C. neoformans (Kamai et al., 2005). MICs of R-135853 against dose-dependent fluconazole-susceptible and fluconazole-resistant strains of C. albicans are 0.03-0.06 |g/mL. R-135853 exhibits dose-dependent efficacy against C. albicans-induced murine experimental hematogenous candidiasis when administered subcutaneously or orally.

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