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Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial and community-acquired pathogen for which few existing antibiotics are efficacious. Here we describe two structurally related synthetic compounds that potentiate beta-lactam activity against MRSA. Genetic studies indicate that these agents target SAV1754 based on the following observations: (i) it has a unique chemical hypersensitivity profile, (ii) overexpression or point mutations are sufficient to confer resistance, and (iii) genetic inactivation phenocopies the potentiating effect of these agents in combination with beta-lactams. Further, we demonstrate these agents inhibit peptidoglycan synthesis. Because SAV1754 is essential for growth and structurally related to the recently reported peptidoglycan flippase of Escherichia coli, we speculate it performs an analogous function in S. aureus. These results suggest that SAV1754 inhibitors might possess therapeutic potential alone, or in combination with beta-lactams to restore MRSA efficacy.

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.

gamma-Pyrone-3-acetic acid (L-741,494) is a novel metabolite produced by a culture of the fungal genus Xylaria. This substance is a water-soluble, competitive, irreversible inhibitor of Interleukin-1 beta Converting Enzyme that is inactive against papain and trypsin. It has a mol wt of 154 and an empirical formula of C7H6O4. We propose the name xylaric acid for this compound.