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 LP3K, 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 LP3K. In a mouse model of polymicrobial infection, LP3K 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.