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However, the development of antimicrobial peptides for clinical applications remains a huge challenge. SPA ([D\u2010rg<jats:sup>1<\/jats:sup>, D\u2010Trp<jats:sup>5,7,9<\/jats:sup>, Leu<jats:sup>11<\/jats:sup>]SP), an analog of substance P, is a broad\u2010spectrum neuropeptide antagonist. In this study, we found that SPA could efficiently kill Gram\u2010positive and Gram\u2010negative bacteria by membrane disruption, similar to antimicrobial peptides. In addition, SPA showed high killing activity toward bacteria rather than mammalian cells. Our results also demonstrated that SPA could significantly decrease the expression of proinflammatory cytokines and rescue mice from lethal septic shock induced by lipopolysaccharide (LPS). The impressive therapeutic potential of SPA, as indicated in this study, makes it a good template for developing effective antibiotics. 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