Engineered Cyclotides with Potent Broad in Vitro and in Vivo Antimicrobial Activity

The search for novel antimicrobial agents to combat microbial pathogens is intensifying in response to the rapid development of drug resistance to current antibiotic therapeutics. Respiratory failure and septicemia are the leading causes of mortality among hospitalized patients. Here, the development of a novel engineered cyclotide with effective broad‐spectrum antibacterial activity against several ESKAPE bacterial strains and clinical isolates is reported. The most active antibacterial cyclotide was extremely stable in serum, showed little hemolytic activity, and provided protection in vivo in a murine model of P. aeruginosa peritonitis. These results highlight the potential of the cyclotide scaffold for the development of novel antimicrobial therapeutic leads for the treatment of bacteremia. The cyclotide is turning: By using a topologically modified sequence of protegrin PG‐1, novel cyclotides were engineered with effective broad‐spectrum antibacterial activity against several ESKAPE bacterial strains and clinical isolates. The most active antibacterial cyclotide showed little hemolytic activity and was extremely stable in serum. In addition, this cyclotide was able to provide protection in vivo in a murine P. aeruginosa‐induced peritonitis model.