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.
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