The Berkeleylactones, Antibiotic Macrolides from Fungal Coculture

A carefully timed coculture fermentation of <i>Penicillium fuscum</i> and <i>P. camembertii/clavigerum</i> yielded eight new 16-membered-ring macrolides, berkeleylactones A–H (<b>1</b>, <b>4</b>, <b>6</b>–<b>9</b>, <b>12</b>, <b>13</b>), as well as the known antibiotic macrolide A26771B (<b>5</b>), patulin, and citrinin. There was no evidence of the production of the berkeleylactones or A26771B (<b>5</b>) by either fungus when grown as axenic cultures. The structures were deduced from analyses of spectral data, and the absolute configurations of compounds <b>1</b> and <b>9</b> were determined by single-crystal X-ray crystallography. Berkeleylactone A (<b>1</b>) exhibited the most potent antimicrobial activity of the macrolide series, with low micromolar activity (MIC = 1–2 μg/mL) against four MRSA strains, as well as <i>Bacillus anthracis</i>, <i>Streptococcus pyogenes</i>, <i>Candida albicans</i>, and <i>Candida glabrata</i>. Mode of action studies have shown that, unlike other macrolide antibiotics, berkeleylactone A (<b>1</b>) does not inhibit protein synthesis nor target the ribosome, which suggests a novel mode of action for its antibiotic activity