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The Novel Azole R126638 Is a Selective Inhibitor of Ergosterol Synthesis in Candida albicans, Trichophyton spp., and Microsporum canis. Hugo Vanden Bossche, 2004.R126638 is a novel triazole with in vitro activity similar to that of itraconazole against dermatophytes, Candida spp., and Malassezia spp . In animal models of dermatophyte infections, R126638 showed superior antifungal activity . R126638 inhibits ergosterol synthesis in Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum, and Microsporum canis at nanomolar concentrations, with 50% inhibitory concentrations (IC50s) similar to those of itraconazole . The decreased synthesis of ergosterol and the concomitant accumulation of 14  -methylsterols provide indirect evidence that R126638 inhibits the activity of CYP51 that catalyzes the oxidative removal of the 14-methyl group of lanosterol or eburicol . The IC50s for cholesterol synthesis from acetate in human hepatoma cells were 1.4 µM for itraconazole and 3.1 µM for R126638 . Compared to itraconazole (IC50 = 3.5 µM), R126638 is a poor inhibitor of the 1-hydroxylation of 25-hydroxyvitamin D3 (IC50 > 10 µM) . Micromolar concentrations of R126638 and itraconazole inhibited the 24-hydroxylation of 25-hydroxyvitamin D3 and the conversion of 1,25-dihydroxyvitamin D3 into polar metabolites . At concentrations up to 10 µM, R126638 had almost no effect on cholesterol side chain cleavage (CYP11A1), 11ß-hydroxylase (CYP11B1), 17-hydroxylase and 17,20-lyase (CYP17), aromatase (CYP19), or 4-hydroxylation of all-trans retinoic acid (CYP26) . At 10 µM, R126638 did not show clear inhibition of CYP1A2, CYP2A6, CYP2D6, CYP2C8, CYP2C9, CYP2C10, CYP2C19, or CYP2E1 . Compared to itraconazole, R126638 had a lower interaction potential with testosterone 6ß hydroxylation and cyclosporine hydroxylation, both of which are catalyzed by CYP3A4, whereas both antifungals inhibited the CYP3A4-catalyzed hydroxylation of midazolam similarly . The results suggest that R126638 has promising properties and merits further in vivo investigations for the treatment of dermatophyte and yeast infections .
Molecular Analysis of Shower Curtain Biofilm Microbes. Scott T. Kelley, 2004.Households provide environments that encourage the formation of microbial communities, often as biofilms . Such biofilms constitute potential reservoirs for pathogens, particularly for immune-compromised individuals . One household environment that potentially accumulates microbial biofilms is that provided by vinyl shower curtains . Over time, vinyl shower curtains accumulate films, commonly referred to as "soap scum," which microscopy reveals are constituted of lush microbial biofilms . To determine the kinds of microbes that constitute shower curtain biofilms and thereby to identify potential opportunistic pathogens, we conducted an analysis of rRNA genes obtained by PCR from four vinyl shower curtains from different households . Each of the shower curtain communities was highly complex . No sequence was identical to one in the databases, and no identical sequences were encountered in the different communities . However, the sequences generally represented similar phylogenetic kinds of organisms . Particularly abundant sequences represented members of the  -group of proteobacteria, mainly Sphingomonas spp . and Methylobacterium spp . Both of these genera are known to include opportunistic pathogens, and several of the sequences obtained from the environmental DNA samples were closely related to known pathogens . Such organisms have also been linked to biofilm formation associated with water reservoirs and conduits . In addition, the study detected many other kinds of organisms at lower abundances . These results show that shower curtains are a potential source of opportunistic pathogens associated with biofilms . Frequent cleaning or disposal of shower curtains is indicated, particularly in households with immune-compromised individuals .
Microbial Characterization of Biofilms in Domestic Drains and the Establishment of Stable Biofilm Microcosms. Andrew J. McBain, 2003.We have used heterotrophic plate counts, together with live-dead direct staining and denaturing gradient gel electrophoresis (DGGE), to characterize the eubacterial communities that had formed as biofilms within domestic sink drain outlets . Laboratory microcosms of these environments were established using excised biofilms from two separate drain biofilm samples to inoculate constant-depth film fermentors (CDFFs) . Drain biofilms harbored 9.8 to 11.3 log10 cells of viable enteric species and pseudomonads/g, while CDFF-grown biofilms harbored 10.6 to 11.4 log10 cells/g . Since live-dead direct staining revealed various efficiencies of recovery by culture, samples were analyzed by DGGE, utilizing primers specific for the V2-V3 region of eubacterial 16S rDNA . These analyses showed that the major PCR amplicons from in situ material were represented in the microcosms and maintained there over extended periods . Sequencing of amplicons resolved by DGGE revealed that the biofilms were dominated by a small number of genera, which were also isolated by culture . One drain sample harbored the protozoan Colpoda maupasi, together with rhabtidid nematodes and bdelloid rotifers . The microcosm enables the maintenance of stable drain-type bacterial communities and represents a useful tool for the modeling of this ecosystem .
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