Development of Broad-Spectrum Antimicrobial Peptides through the Conjugation of FtsZ-Binding and Cell-Penetrating Peptides

The rapid increase in bacterial resistance to conventional antibiotics has led to a great demand for novel antibacterial agents. Antimicrobial peptides (AMPs) are emerging as next-generation antimicrobial alternative drugs to conventional antibiotics because of their broad-spectrum antimicrobial activities and minimal potential for drug resistance induction. This work describes novel antimicrobial peptides (FtsZpcpp) synthesized through the conjugation of a cell penetration peptide ((RXR)₄XB) to nonantimicrobial peptides (FtsZp). The FtsZp peptides were previously identified to bind FtsZ (flaming-temperature-sensitive protein Z), a crucial protein in regulating bacterial cell divisions. Newly designed FtsZpcpp peptides have broad antimicrobial activities against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. Besides, these new peptides exert minimal hemolytic activity toward human red blood cells and low cytotoxicity toward human skin cells. Comprehensive studies on the antimicrobial mechanism of FtsZpcpp peptides revealed that they exert antimicrobial activities through multiple mechanisms, including membrane disruption and intracellular actions (e.g., interference with cell divisions, DNA binding, and reactive oxygen species (ROS) generation). Our results have shown that FtsZpcpp peptides have the potential to serve as future antimicrobial drugs in combating the increasing global problem of antibiotic resistance.