Sordarins Inhibit Aspergillus fumigatus Protein Synthesis.



Sensitivity of Aspergillus fumigatus protein synthesis machinery to sordarin antifungals has been assessed by using a cell-free translation system. Preparation of such a system is highly dependent on the culture conditions of the filamentous fungi. One of the difficulties in setting up the system may arise from the existence of endogenous protein synthesis inhibitors, that has been previously reported in other Aspergillus spp. We have investigated and standardized growth conditions that allow preparation of translational systems and optimized assay conditions for efficient and reproducible synthesis of poly-Phe directed from poly-U as synthetic mRNA template. Several sordarin derivatives have demonstrated submicromolar activity to inhibit the system, GM 222712A being the most potent compound (IC50 = 0.1 micro g/mL). Purified elongation factor 2 (EF-2) from A. fumigatus has been used to functionally reconstitute C. albicans translational systems that had been inactivated by specific EF-2 depletion with diphteria toxin. Since the profile of sensitivity to sordarin compounds of these heterologous systems is dependent upon the source of EF-2, it is proposed that, as in C. albicans, EF-2 function is the target of this class of antifungals in Aspergillus fimigatus.

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38th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 38th