Daptomycin and Calcium: How an anionic peptide targets an anionic membrane. The mechanism of action of Daptomycin has been described as a lipid-extracting effect by Chen et al. , with the decanoyl moiety at the N-terminus playing a central role in this process. In addition to its lipid-extracting activity, Daptomycin may also interact with bacterial membrane proteins, such as Usp2, leading to increased reactive oxygen species (ROS) production that results in bacterial cell death . The development of Daptomycin resistance has been associated with several factors, including cell wall thickening, alterations in membrane lipid composition, and changes in membrane fluidity . Karas et al. provided a comprehensive structure-activity relationship (SAR) map for Daptomycin, highlighting the importance of the DxDG motif in forming a Ca 2+ -mediated complex that is fundamental for Daptomycin's activity , while other structural features are potentially modifiable to tweak the activity spectra and to improve the pharmacokinetic (PK) profile.