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Cytomegalovirus infections are an important cause of disease for which no licensed vaccine exists. Recent studies have focused on the gH/gL/UL128-131 complex as antibodies to gH/gL/UL128-131 neutralize viral entry into epithelial cells. Prior studies have used cells from the retinal pigment epithelium, while to prevent transmission, vaccine-induced antibodies may need to block viral infection of epithelial cells of the oral or genital mucosa. We found that gH/gL/UL128-131 is necessary for efficient viral entry into epithelial cells derived from oral and genital mucosa, that short peptides from UL130 and UL131 elicit high titer neutralizing antibodies in rabbits, and that such antibodies neutralize viral entry into epithelial cells derived from these relevant tissues. These results suggest that single subunits or peptides may be sufficient to elicit potent epithelial entry neutralizing responses and that secretory antibodies to such neutralizing epitopes have the potential to provide sterilizing immunity by blocking initial mucosal infection.

The reaction of 5-(1-adamantyl)-4-amino-3-mercapto-1,2,4-triazole (5) with various aromatic aldehydes in ethanol or acetic acid yielded the corresponding 4-arylideneamino derivatives 6a–v. Treatment of the 4-(2,6-difluoro- and dichlorobenzylideneamino) derivatives 6o and 6q with 1-substituted piperazines, and formaldehyde solution in ethanol afforded good yields of the corresponding 5-(1-adamantyl)-4-(2,6-dihalobenzylideneamino-2-(4-substituted-1-piperazinylmethyl)-1,2,4-triazoline-3-thiones 7a–p. 5-(1-Adamantyl)-4-arylideneamino-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-triazoline-3-thiones 8a–n, were similarly prepared via the reaction of the corresponding arylideneamino derivative with ethyl 4-piperidinecarboxylate and formaldehyde solution in ethanol. Compounds 6a–v, 7a–p and 8a–n were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several derivatives showed good or moderate activities, particularly against the tested Gram-positive bacteria. In addition, the in vivo anti-inflammatory activity of 21 compounds was determined using the carrageenan-induced paw oedema method in rats. Compounds 7d, 7g, 7i, 7j, 7l, 8c, 8e and 8l showed good or moderate dose-dependent activity in this area.

Hygromycin A, an antibiotic produced by Streptomyces hygroscopicus NRRL 2388, offers a distinct carbon skeleton structure for development of antibacterial agents targeting the bacterial ribosomal peptidyl transferase. A 31.5 kb genomic DNA region covering the hygromycin A biosynthetic gene cluster has been identified, cloned, and sequenced. The hygromycin gene cluster has 29 ORFs which can be assigned to hygromycin A resistance as well as regulation and biosynthesis of the three key moieties of hygromycin A (5-dehydro-alpha-L-fucofuranose, (E)-3-(3,4-dihydroxyphenyl)-2-methylacrylic acid, and 2L-2-amino-2-deoxy-4,5-O-methylene-neo-inositol. The predicted Hyg26 protein has sequence homology to short-chain alcohol dehydrogenases and is assigned to the final step in production of the 5-dehydro-alpha-L-fucofuranose, catalyzing the reduction of alpha-L-fucofuranose. A hyg26 mutant strain was generated and shown to produce no hygromycin A but 5''-dihydrohygromycin A, 5''-dihydromethoxyhygromycin A, and a 5''-dihydrohygromycin A product lacking the aminocyclitol moiety. To the best of our knowledge, these shunt metabolites of biosynthetic pathway intermediates have not previously been identified. They provide insight into the ordering of the multiple unusual steps which compromise the convergent hygromycin A biosynthetic pathway.

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