Phosphate-Binding Zn(II)-Coordinated Antimicrobial Peptoids: Enhancing Selectivity through Specific Recognition of Bacterial Membranes.

The global spread of multidrug-resistant bacteria underscores the urgent need for antimicrobial agents with enhanced efficacy and selectivity. Here, we developed antimicrobial peptoids conjugated with zinc-dipicolylamine (ZnDPA) and bivalent Zn2BPMP motifs for improved bacterial membrane recognition via phosphate binding. The Zn2BPMP-containing peptoids, 5_Zn2 and 8_Zn4, exhibited the highest bacterial selectivity, achieving an increase in selectivity index of >10-fold. Cytotoxicity assays confirmed reduced toxicity against mammalian cells. Mechanistically, Zn2BPMP conjugation enhanced binding to anionic bacterial surface components, including lipopolysaccharides and lipoteichoic acids, and promoted inner membrane disruption. Furthermore, in a model of multidrug-resistant E. coli-induced sepsis, 5_Zn2 exhibited potent antimicrobial and anti-inflammatory activity with low in vivo toxicity and therapeutic efficacy. These findings provide insights into the rational design of antimicrobial peptoids and peptidomimetics to selectively target bacteria and highlight their potential as next-generation therapeutics.