Svetamycins A–G, Unusual Piperazic Acid-Containing Peptides from Streptomyces sp.

Denis Dardić, Gianluigi Lauro, Giuseppe Bifulco, Patricia Laboudie, Peyman Sakhaii, Armin Bauer, Andreas Vilcinskas, Peter E. Hammann, Alberto Plaza

Index: 10.1021/acs.joc.7b00228

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Abstract

Seven new halogenated peptides termed svetamycins A–G (1–7) have been isolated from laboratory cultures of a Streptomyces sp. Svetamycins A–D, F, and G are cyclic depsipeptides, whereas svetamycin E is a linear analogue of svetamycin C. Their structures were determined using extensive spectroscopic analysis, and their stereochemical configuration was established by a combination of NMR data, quantum mechanical calculations, and chemical derivatizations. Svetamycins are characterized by the presence of a hydroxyl acetic acid and five amino acids including a rare 4,5-dihydroxy-2,3,4,5-tetrahydropyridazine-3-carboxylic acid, a γ-halogenated piperazic acid, and a novel δ-methylated piperazic acid in svetamycins B–C, E, and G. Moreover, isotope-labeled substrate feeding experiments demonstrated ornithine as the precursor of piperazic acid and that methylation at the δ position of the piperazyl scaffold is S-adenosyl-l-methionine (SAM)-dependent. Svetamycin G, the most potent antimicrobial of this suite of compounds, inhibited the growth of Mycobacterium smegmatis with an MIC80 value of 2 μg/mL.