A Bioinspired Lipopeptide Surmounts Therapeutic Dilemmas of Gram-Positive and Gram-Negative Polymicrobial Infection

Polymicrobial infections present considerable therapeutic challenges due to the absence of effective antimicrobial agents, particularly those involving both Gram-positive and Gram-negative bacteria. We hypothesize that antimicrobials rationally designed to target both the outer and inner membranes─distinct structural differences between these bacteria─could offer solutions to the therapeutic dilemmas of polymicrobial infections. Through lipid screening, we identified a promising lipid scaffold capable of disrupting the membrane system of both Gram-positive and Gram-negative bacteria. We developed a chemical optimization strategy to design an inverted-conical lipopeptide of LP^3K, which exhibits broad-spectrum antimicrobial activity against polymicrobial infections without the emergence of resistance. We further elucidated the structure-activity relationship and antimicrobial mechanisms of LP^3K. In a mouse model of polymicrobial infection, LP^3K demonstrated substantial antimicrobial and therapeutic effects, with confirmed in vivo biosafety. Our findings highlight the potential of lipopeptides as clinically translatable antimicrobials for the effective treatment of polymicrobial infections.