The fungus racemosus is able to phenotypically adapt to the antifungal compounds cycloheximide (CHX) and trichodermin (TDM) after a brief period of adaptation (see Figure 1 for structures). Exposure to either inhibitor results in the simultaneous activation of at least two different resistance mechanisms: enzymatic degradation of TDM via a TDM-esterase and active efflux of CHX. The efflux of CHX is similar to the efflux systems seen in multi-drug resistant mammalian tumor cells which over-express P-glycoprotein (PG), an energy dependent efflux pump with a broad substrate range. Adapted cells grown in the absence of inhibitors de-adapt after several hours. Similar phenotypic multi-drug resistance systems may be more common than currently thought and may be an important impediment to the control of microbes with antibiotics or disinfectants Thus Mucor may serve as an important model for phenotypic resistance systems in microorganisms. The long term goal of this research is to understand the molecular biology of the adaptive. This proposal focuses mainly on the active efflux on CHX with the following specific aims: (1.) Complete the sequencing and analysis of the MPG, (2.) Study the expression of MPG in response to chemical and physical stress. (3.) Test the hypothesis that the MPG is the CHX efflux protein.
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