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, <b>5_Zn</b>_<b>2</b> and <b>8_Zn</b>_<b>4</b>, 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 <i><i>E. coli</i></i>-induced sepsis, <b>5_Zn</b>_<b>2</b> exhibited potent antimicrobial and anti-inflammatory activity with low <i>in vivo</i> 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.