Premium
Regiospecific Synthesis of Calcium‐Independent Daptomycin Antibiotics using a Chemoenzymatic Method
Author(s) -
Mupparapu Nagaraju,
Lin YuHsin Cindy,
Kim Tae Ho,
Elshahawi Sherif I.
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202005100
Subject(s) - pharmacophore , daptomycin , antibiotics , chemistry , residue (chemistry) , derivatization , calcium , combinatorial chemistry , stereochemistry , molecule , bacteria , biochemistry , staphylococcus aureus , organic chemistry , biology , vancomycin , high performance liquid chromatography , genetics
Daptomycin (DAP) is a calcium (Ca 2+ )‐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 Ca 2+ ‐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.