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 analogs. In order to mimic the Ca2+‐binding effect we uses a chemoenzymatic approach to modify the tryptophan (Trp) residue of DAP and synthesize kinetically characterized and structurally elucidated regiospecific Trp‐modified DAP analogs. We demonstrated that the modified DAPs are several‐folds 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.
Mupparapu N, Lin YC, Kim TH, Elshahawi SI. Regiospecific synthesis of calcium-independent daptomycin antibiotics using a chemoenzymatic method. Chemistry. 2020;10.1002/chem.202005100. https://doi.org/10.1002/chem.202005100