Microbes are a rich source of bioactive metabolites; they represent a wide variety of chemical structures and specific biological activities. In our continuing search for bioactive metabolites from microbes, a culture broth of an actinomycete strain of the genus Streptomyces, from which several bioactive secondary metabolites were isolated, was found to contain a novel antimicrobial lipodepsipeptide, designated pentadepsin A (1). Herein, we report the isolation, structure elucidation and biological activity of pentadepsin A. The molecular formula of 1 was established as C37H57N508 on the basis of HR-FABMS and NMR spectral data. The planar structure of 1 was elucidated by 2D NMR analysis; it represented a sixteen-membered ring system, consisting of five amino acids, to which a unique acyl group 2,4-dimethyl heptanoic acid (Dmh) was linked through an amide bond. The absolute stereochemistry of amino acid residues was determined by advanced Marfey's method, while that of Dmh residue was partially elucidated by PGME method. For the full elucidation of the side chain structure, (2S,4R)-Dmh and (2S,4S)-Dmh were synthesized via Evans alkylation. Spectroscopic comparison of Dmh obtained from 1 with the synthesized ones revealed that the side chain of 1 is (2S,4S)-2,4-dimethylheptanoic acid. Pentadepsin A selectively inhibited cell growth of Streptomyces species, while exhibited no growth inhibition against other bacteria tested and no cytotoxic effect mammalian cells. Detailed analysis of the mechanism of action of pentadepsin A is underway.
