Modular synthesis of daptomycin analogues

Daptomycin is an antimicrobial peptide that is a last-line drug for Gram-positive bacterial infections. However, the emergence of daptomycin resistant strains underscores the need to develop more effective analogues. The molecule contains a depsi-bond within a 31-atom macrocycle and a fatty acyl chain at the N-terminus. Solid-phase peptide synthesis provides an effective approach for generating analogues, yet the structural complexity of daptomycin presents several production challenges for their efficient preparation. Herein, we report a modular synthesis of daptomycin analogues that is particularly suitable for producing variants modified at the N-terminus, L-Trp1 and L-Orn6. A key finding of this study is that macrocyclisation yields are vastly improved when this step in conducted prior to N-terminal lipidation. Moreover, antimicrobial activity against Staphylococcus aureus is largely retained when both L-3-MeGlu12 and L-Kyn13 are replaced with readily available L-Glu12 and L-Trp13, which simplifies synthesis considerably. We anticipate that our new method will fast-track the development of new daptomycin analogues with improved antimicrobial and pharmacokinetic properties.