Total Synthesis of Malacidin A by β-Hydroxyaspartic Acid Ligation-Mediated Cyclization and Absolute Structure Establishment

Angew Chem Int Ed Engl. 2020 Nov 2;59(45):19868-19872. doi: 10.1002/anie.202009092. Epub 2020 Aug 31.

Abstract

The development of novel antibiotics is critical to combating the growing emergence of drug-resistant pathogens. Malacidin A is a new member of the calcium-dependent antibiotic (CDAs) family with activity against antibiotic-resistant pathogens. Its mode of action is distinct from classical CDAs. However, the absolute structure of malacidin A has not been established. Herein, the total syntheses of malacidin A and its analogues are reported by a combination of Fmoc-based solid-phase peptide synthesis (SPPS) and β-hydroxyaspartic acid ligation-mediated peptide cyclization. The total synthesis enabled us to establish the absolute configuration of malacidin A, which is in agreement with those for natural malacidin A confirmed by advanced Marfey's analysis in our study.

Keywords: chemical ligation; cyclic peptide antibiotics; malacidin; total synthesis; β-hydroxyaspartic acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / chemistry
  • Cyclization*
  • Lipopeptides / chemical synthesis*
  • Molecular Structure
  • Peptides, Cyclic / chemical synthesis*
  • Solid-Phase Synthesis Techniques
  • Stereoisomerism

Substances

  • Lipopeptides
  • Peptides, Cyclic
  • malacidins
  • 3-hydroxyaspartic acid
  • Aspartic Acid