ecumicin and Tuberculosis

The ohmyungsamycin and ecumicin natural product families are structurally related cyclic depsipeptides that display potent antimycobacterial activity. Herein the total syntheses of ohmyungsamycin A, deoxyecumicin, and ecumicin are reported, together with the direct biological comparison of members of these natural product families against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). The synthesis of each of the natural products employed a solid-phase strategy to assemble the linear peptide precursor, involving a key on-resin esterification and an optional on-resin dimethylation step, before a final solution-phase macrolactamization between the non-proteinogenic N-methyl-4-methoxy-l-tryptophan amino acid and a bulky N-methyl-l-valine residue. The synthetic natural products possessed potent antimycobacterial activity against Mtb with MIC

Topics: Antitubercular Agents; Humans; Mycobacterium tuberculosis; Peptides, Cyclic; Tuberculosis

The new tuberculosis (TB) lead ecumicin (1), a cyclic tridecapeptide, was isolated from Nonomuraea sp. MJM5123, following a high-throughput campaign for anti-TB activity. The large molecular weight of 1599 amu detected by LC-HR-MS precluded the initial inference of its molecular formula. The individual building blocks were identified by extensive NMR experiments. The resulting two possible planar structures were distinguished by LC-MS(2). Determination of absolute configuration and unambiguous structural confirmation were carried out by X-ray crystallography and Marfey's analysis.

Topics: Antineoplastic Agents; Chromatography, Liquid; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Peptides, Cyclic; Tuberculosis