Revision of the full stereochemistry of telomycin

Abstract

Telomycin, a nonribosomal cyclic depsipeptide antibiotic discovered in the late 1950s, has recently been shown to display a unique lytic mode of action based on a specific interaction with the bacterial dimeric phospholipid cardiolipin. Noticeably, the bibliography dealing with the chemical structure and natural occurrence of telomycin and related congeners reveals important contradictions that put into question the currently accepted all L-amino acid stereochemistry for this antibiotic. Furthermore, the configuration at C_β of its β-MeTrp residue remains undetermined and the olefin geometry of its Δ_2,3-Trp residue likewise demands clarification. A full revision of the relative and absolute stereochemistry of telomycin amino acids, also including the unambiguous determination of the sequence position of the diastereomeric residues present in this exciting antibiotic, was thus needed. Herein, we have ascertained the enantioselectivity of the canonical condensation domains involved in telomycin biosynthesis by phylogeny-based bioinformatic analysis of its nonribosomal peptide synthetases sequence and we have also carried out rigorous chiral amino acid analysis, by NMR and the advanced Marfey's method, to unequivocally determine the correct structure and absolute stereochemistry of the antibiotic, leading to a definitive stereochemical revision of the telomycin family.