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A novel low-molecular weight inhibitor of an aminoglycoside-inactivating enzyme, initially THE JOURNAL OF ANTIBIOTICS

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An inhibitor of dopamine-/3-hydroxylase, designated A32390A, was isolated from the culture broth of a Pyrenochaeta species. The inhibitor showed antimicrobial activity against fungi and gram-positive bacteria. Spectroscopic analysis and chemical degradation studies indicated that the structure was 1,6-di-O-(2-isocyano-3-methylcrotonyl)-n-mannitol.In the course of screening for microorganisms that produce dopamine-,8-hydroxylase inhibitors, a culture was found that produced several compounds that inhibited the enzyme. The producing organism (NRRL 5786) was classified as a strain of the genus Pyrenochaeta in the order Sphaeropsidales.Fermentation conditions for the production of the inhibitor are described in the preceding papery. A thin-layer chromatogram of filtered broth is shown in Fig. 1. Chromatograms were developed on pre-coated Merck silica gel F-254 plates using chloroform -methanol (9: 1) as the mobile phase in a saturated chamber. The components were visualized using iodine vapor, short wavelength UV light, or by bioautography on Micrococcus luteus. Four compounds, designated A32390A, B, C and D, were detected by bioautography. The total amount of these compounds in the broth was estimated by microbiological assay to be 60 ug/ml. Isolation of A32390AThe procedure for the isolation of A32390A is shown schematically in Fig. 2. Hyflo Supercel was added to whole broth which was then filtered to remove the mycelia. The broth filtrate was extracted twice with ethyl acetate at harvest pH and the combined extracts were concentrated to approximately I % of the original broth volume. When the concentrates were cooled, a precipitate formed that was 75Y. by weight A32390A. The precipitate was collected and chromatographed on a Grade 62 silica gel column using ethyl acetate as the eluant. Fractions were monitored microbiologically using M.htteus as the assay organism. The active fractions were combined, concentrated, and cooled