Perhaps the most striking difference between fungal cells and human cells is that fungal cells are encased in a wall that protects them from a hostile external environment. The cell wall plays a dynamic role in all aspects of fungal physiology. The fact that human cells lack a cell wall and the underlying biosynthetic and regulatory machinery to make the wall, suggests that drugs targeting cell-wall synthesis and assembly will be safe and specific antifungals. Current treatments include Amphotericin B and a variety of azoles that inhibit membrane-sterol biosynthesis. Unfortunately, Amphotericin B is toxic to humans and clinical resistance to azoles is increasing. These observations underscore the clear need for new antifungals. In this Phase I SBIR application, we propose to develop a novel screen that targets an essential step in fungal cell-wall assembly, namely, the extracellular anchorage of GPI-class mannoproteins. This will be accomplished in two specific aims: 1). Development of a screen to detect inhibitors of GPI-mannoprotein anchoring into the cell wall; 2). Screening of extracts for inhibitors using the assay developed in Aim One.
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