The increasing incidence of life-threatening fungal infections has driven the search for new, broad-spectrum fungicidal agents that can be used for treatment and prophylaxis in immunocompromised patients. Naturalproduct inhibitors of cell wall (

Pretreatment of yeast cells with lithium acetate (LiAc) and dithiothreitol (DTT) enhances the frequency of transformation by electroporation. The method shows improvements of 6–67‐fold in wild‐type strains derived from commonly used Saccharomyces cerevisiae genetic backgrounds. In addition, 15–300‐fold improvement in transformation frequency was achieved with several mutant strains of S. cerevisiae that transformed poorly by conventional procedures. Both DTT and lithium acetate were necessary for maximal transformation frequencies. Pretreatment with lithium and DTT also resulted in an ∼3·5‐fold increase in the electroporation transformation frequency of the pathogenic fungus Candida albicans. © 1998 John Wiley & Sons, Ltd.

Potent antifungal activity was detected in fermentation extracts of Sporormiella australis and two related components were isolated from solid fermentations using silica gel and high speed countercurrent chromatography. The most active antifungal component, australifungin, contained a unique combination of a-diketone and jS-ketoaldehyde functional groups. Australifungin exhibited broad spectrum antifungal activity against humanpathogenic fungi with MICs against Candida spp., Cryptococcus neoformans, and Aspergillus spp. between 0.01 5 and 1.0 //g/ml. Modeof action studies revealed that australifungin interfered with fungal lipid metabolism by specifically inhibiting sphingolipid synthesis at the step converting sphinganine to ceramide.

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A family of'aminoacyl alkyl citrate compounds called viridiofungins, are novel squalene synthase inhibitors. The compounds have broad spectrum fungicidal activity but lack antibacterial activity. Although the compoundsinhibit squalene synthase, the first committed step in ergosterol biosynthesis, results presented in this paper show that inhibition of fungal growth is not related to inhibition of ergosterol synthesis.The preceding paper described the isolation and structure elucidation of novel amino alkyl citrate compounds called viridiofungins^.The compounds which inhibit squalene synthase have broad spectrum antifungal activity but lack antibacterial activity. This paper describes the results showing that the antifungal mode of action of these compounds is unrelated to inhibition of ergosterol synthesis despite the fact that viridiofungins inhibit squalene synthase. Methods FermentationCulture MF 5628 {Trichoderma viride) produced viridiofungin. The compoundwas produced in a two stage fermentation process consisting of growth in seed medium A2) followed by subsequent product fermentation in appropriate fermentation media. Frozen vegetative mycelia (FVM)of the culture were prepared and used to inoculate flasks of seed medium A. Substantial vegetative fungal growth was obtained from seed flasks after 45~48 hours incubation at 25°C on gyratory shaker (220 rpm). Production flasks were inoculated by aseptic transfer of 2 mis of seed growth and were incubated at 25°C in a medium consisting of yellow cornmeal, 50.0g/ liter; yeast extract, l.Og/liter; and sucrose, 80.0g/liter; dispensed 45 ml/nonbaffied 250-ml Erlenmeyer flask. Flasks were agitated at 220rpmon a gyratory shaker.

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