Pneumocystis carinii (Pc) pneumonia is a common and lethal opportunistic infection in AIDS. Pc pneumonia is recurrent; when drug therapy is stopped, the Pc pneumonia recurs. Pc cysts are believed to play an important part in infection, activation and re-activation of the disease. A Beta 1->3 glucan forms the thick inner layer of Pc cyst walls. Purified cultured Pc organisms contain a very active Beta 1->3 D glucan synthase which is probably involved in the biosynthesis of the cell wall glucan. It is proposed to test the hypothesis that the addition of Beta 1->3 glucan cell wall inhibitors to conventional anti-Pc during therapy will alter or modulate the relapsing nature of the Pc infection. The Pc enzyme exhibiting Beta 1->3 D glucan synthase activity will be characterized. We will attempt to inhibit the Pc glucan synthase activity in vitro using members of several classes of inhibitors known to interfere with Beta 1->3 D glucan synthesis in other organisms. Suitable inhibitors will be selected from the in vitro study and will be studied in rats infected with Pc, in order to assess Pc cyst survival and disease recurrence. It is also proposed to clone the Pc synthase gene into E. coli and to express the gene product. This is a preliminary step for the eventual study of the control of cell wall synthesis in Pneumocystis carinii.
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