LAUSR

Herein, we report the synthesis and antibacterial evaluation of a series of daptomycin lactam‐based analogues. As compared with daptomycin, the daptomycin analogue with singly modified lactam has an eightfold increase in its minimum inhibitory concentration (MIC) against methicillin‐resistant Staphylococcus aureus. Incorporating effective modifications found in previous daptomycin structure–activity relationship studies to produce lactam‐based analogues with multiple modifications did not improve the antibacterial activity of the analogues. Instead, the antibacterial activity was greatly reduced when a rather rigid 4‐(phenylethynyl)benzoyl group replaced the flexible n‐decanoyl group. The fact that the lactam analogue with the 4‐(phenylethynyl)benzoyl group did not exhibit the antibacterial activity comparable to the two respective singly modified analogues showed that the inactivity was probably due to the deviation from the active conformation. This series of lactam analogues may generate insights on the importance of studying the active conformation of daptomycin and how the structural modifications affect the active conformation.