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Many fundamental biological processes occur on cell membranes, and a typical example is the membrane permeabilization by peptides for an antimicrobial purpose. Previous studies of the underlying mechanism mostly focus on structural changes of membranes and peptides during their interactions. Herein, from a new perspective of single-molecule dynamics, the real-time three-dimensional motions of individual phospholipid and peptide molecules were monitored, and specifically, their correlation with the membrane poration function of melittin, a most representative natural antimicrobial peptide, was studied. We found that the adsorption and accumulation of melittin on the membrane surface significantly sped up the lateral diffusion of lipids surrounding the peptides, which in turn facilitated the peptide insertion at such heterogeneous regions. A unique "U"-bending pathway of melittin during membrane insertion and the ultimate formation of toroidal pores with dynamical translocations of peptides and lipids with several metastable states between the two leaflets of bilayer were observed.

Addressing the devastating threat of drug-resistant pathogens requires the discovery of new antibiotics with advanced action mechanisms and/or novel strategies for drug design. Herein, from a biophysical perspective, we design a class of synthetic antibacterial complexes with specialized architectures based on melittin (Mel), a natural antimicrobial peptide, and poly(ethylene glycol) (PEG), a clinically available agent, as building blocks that show potent and architecture-modulated antibacterial activity. Among the complexes, the flexibly linear complex consisting of one Mel terminally connected with a long-chained PEG (e.g., PEG12k–1*Mel) shows the most pronounced improvement in performance compared with pristine Mel, with up to 500% improvement in antimicrobial efficiency, excellent in vitro activity against multidrug-resistant pathogens (over a range of minimal inhibitory concentrations of 2–32 µg mL−1), a 68% decrease in in vitro cytotoxicity, and a 57% decrease in in vivo acute toxicity. A lipid-specific mode of action in membrane recognition and an accelerated “channel” effect in perforating the bacterial membrane of the complex are described. Our results introduce a new way to design highly efficient and low-toxicity antimicrobial drugs based on architectural modulations with clinically available agents.