Regiospecific Synthesis of Calcium-Independent Daptomycin Antibiotics using a Chemoenzymatic Method

Chemistry. 2021 Feb 24;27(12):4176-4182. doi: 10.1002/chem.202005100. Epub 2021 Jan 26.


Daptomycin (DAP) is a calcium (Ca2+ )-dependent FDA-approved antibiotic drug for the treatment of Gram-positive infections. It possesses a complex pharmacophore hampering derivatization and/or synthesis of analogues. To mimic the Ca2+ -binding effect, we used a chemoenzymatic approach to modify the tryptophan (Trp) residue of DAP and synthesize kinetically characterized and structurally elucidated regiospecific Trp-modified DAP analogues. We demonstrated that the modified DAPs are several times more active than the parent molecule against antibiotic-susceptible and antibiotic-resistant Gram-positive bacteria. Strikingly, and in contrast to the parent molecule, the DAP derivatives do not rely on calcium or any additional elements for activity.

Keywords: antibiotics; biological activity; enzymes; natural products; reaction mechanisms.

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Calcium
  • Daptomycin*
  • Gram-Positive Bacteria
  • Microbial Sensitivity Tests


  • Anti-Bacterial Agents
  • Daptomycin
  • Calcium