We have used the filamentous fungus, Neurospora crassa, as a model system to test the concept that antisense targeting of the cell-wall assembly enzyme, (1,3)beta-glucan synthase [E.C. 2.4.1.34; UDPglucose: 1,3-beta-D-glucan 3-beta-D-glucosyltransferase], leads to a corresponding decrease in growth of the organism. Previously, our laboratory isolated a gene (glucan synthase-1, gs-1) that is required for (1,3)beta-glucan synthase activity. Wild-type cells were transformed with DNA vectors encoding various RNAs complementary to the gs-1 messenger RNA (antisense RNA) cloned downstream from an inducible promoter (quinic acid-2[qa-2p]). Stable transformants, expressing a partially inverted antisense message of gs-1 (pMYX107), exhibited dramatic reduction ingrowth compared with empty vector controls. Hyphal measurements of these transformants grown on race tubes indicated that all of the transformants showed various degrees of inhibition. Microscopic observations of transformants revealed shorter hyphal lengths when grown under conditions expressing antisense. Further characterization revealed that the specific activities of (1,3)beta-glucan synthase were decreased by as much as 63% relative to empty vector controls. Together, these observations suggest that antisense against (1,3)beta-glucan synthase led to a reduction in enzyme levels that resulted in altered cell-wall morphology and inhibition of growth. It is possible that antisense oligonucleotides against gs-1 may be useful antifungal agents.
sodium salt, 5mM NaF, 250mM sucrose, and 10 mM NaH2PO4; and for A. fumigatus, 50mM HEPES, 10mM EDTA, 750mM sucrose, 10mM NaH2PO4, 100mM cellobiose and During the last three decades there has been a dramatic increase in the frequency of fungal infections, especially disseminated systemic mycoses in immunodeficient hosts1,2). Mycoses in compromised hosts are mainly the result of opportunistic infections by organisms that are normally harmless, asymptomatic commensals which can be, under certain conditions, pathogenic3,4). Species of Aspergillus, Candida, Coccidioides, Cryptococcus, Histo
expected to result in negligible alterations in the unbound drug as represented in our current patient profiles. On the basis of these data, we conclude that intravenous doripenem 500 mg once every 24 hours provides adequate concentrations throughout the dosing interval in patients with ESRD undergoing hemodialysis; however, controlled pharmacokinetic studies should be performed to confirm the best dosing strategy in this population and assess potential drug accumulation.
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