A Chirality‐Converted Bacteriolytic Dodecapeptide Regulates <i>Vibrio</i> ‐Induced Polymicrobial Infection and Ameliorates Invasion‐Associated Gut Microbiota Disequilibrium

The polymicrobial infections caused by Vibrio species, especially multidrug-resistant isolates, are posing increasing threats to the health of coastal residents. Herein, a novel dodecapeptide, denoted as D-zp37, was designed and synthesized, aiming to combat these notorious pathogens. Experimental results proved that the simple chirality conversion of the parent peptide, zp37, could significantly boost the antibacterial activity and proteolytic stability. To a specific cephalosporin-resistant Vibrio alginolyticus, the minimal inhibitory concentration value of D-zp37 was as low as 0.5 µm. Beyond the strong bacteriolytic effect against planktonic Vibrio alginolyticus, Vibrio parahaemolyticus and Vibrio vulnificus strains, D-zp37 was found to restrain the biofilm establishment of Vibrio mixtures via inhibiting the efflux of intracellular polysaccharides. Mechanistic studies hinted that D-zp37 impeded the electron transport chain, impaired the membrane stress response by downregulating the phage shock protein family, and blocked amino acid biosynthesis in Vibrio cells. Furthermore, three different infection models (shrimp, Galleria mellonella larvae and immunosuppressed mice) collaboratively confirmed the anti-Vibrio efficacy of D-zp37 in vivo. In addition, the intragastric administration of D-zp37 was found to be beneficial in restoring the imbalanced gut microbiota induced by the polymicrobial Vibrio invasion. In summary, this work investigated the antibacterial mechanisms and in vivo efficacy of a novel peptide lead compound, proposing a new therapeutic against Vibrio infections.