There is substantial interest in exploring antibiotic alternatives with a new mode of action due to the increasing rates of bacterial resistance against current antibiotics. Antimicrobial peptides (AMPs) may take up the battle against bacteria in the future because as a result of their membrane-lysis mechanism, it is more difficult for bacteria to develop resistance against AMPs. Although AMPs could preferentially bind to and disrupt negatively charged bacterial membranes through electrostatic and hydrophobic interactions, there is still a great need to further increase the potency and selective toxicity towards bacteria for clinical applications. Herein, we present two strategies to improve the selectivity: light activation and environment-responsive moiety incorporation. Along the way, we also explored the effect of structure stabilization on AMPs action. A well-characterized antimicrobial peptide magainin 2 (mag2) was used as a prototype. Chemical manipulations of mag2 sequence were achieved by incorporation of unnatural amino acids. The selectivity was then tested on liposomes as a membrane model, as well as on bacterial cells and human red blood cells (hRBCs). Different extents of selectivity enhancement were observed from the modified peptides, and within the attempts to illustrate these results, we have gained useful information revealing the membrane-lysis mechanism, which may help us to rationally design and engineer AMPs as therapeutic drugs in the future.
