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Respiratory failure and septicemia are the leading causes of mortality among hospitalized patients. Here, the development of a novel engineered cyclotide with effective broad\u2010spectrum 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\u2005vivo in a murine model of\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    peritonitis. 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