Imidazole‐Rich, Four‐Armed Host‐Defense Peptidomimetics as Promising Narrow‐Spectrum Antibacterial Agents and Adjuvants against Pseudomonas Aeruginosa Infections

The development of narrow‐spectrum antimicrobial agents is paramount for swiftly eradicating pathogenic bacteria, mitigating the onset of drug resistance, and preserving the homeostasis of bacterial microbiota in tissues. Owing to the limited affinity between the hydrophobic lipid bilayer interior of bacterial cells and most hydrophilic, polar peptides, the construction of a distinctive class of four‐armed host‐defense peptides/peptidomimetics (HDPs) is proposed with enhanced specificity and membrane perturbation capability against Pseudomonas aeruginosaby incorporating imidazole groups. These groups demonstrate substantial affinity for unsaturated phospholipids, which are predominantly expressed in the cell membrane of P. aeruginosa, thereby enabling HDPs to exhibit narrow‐spectrum activity against this bacterium. Computational simulations and experimental investigations have corroborated that the imidazole‐rich, four‐armed peptidomimetics exhibit notable selectivity toward bacteria over mammalian cells. Among them, 4H10, characterized by its abundant and densely distributed imidazole groups, exhibits impressive activity against various clinically isolated P. aeruginosastrains. Moreover, 4H10 has demonstrated potential as an antibiotic adjuvant, enhancing doxycycline accumulation and exerting effects on intracellular targets by efficiently disrupting bacterial cell membranes. Consequently, the hydrogel composed of 4H10 and doxycycline emerged as a promising topical agent, significantly diminishing the skin P. aeruginosaburden by 97.1% within 2 days while inducing minimal local and systemic toxicity. Imidazole‐rich four‐armed peptidomimetics are synthesized as narrow‐spectrum antibacterial agents and adjuvants targeting Pseudomonas aeruginosa. This article highlights the pivotal role of the copious and densely packed imidazole groups within the star‐shaped polypeptide structure in interacting with unsaturated phospholipids in the cell membrane of P. aeruginosa. Consequently, these interactions facilitate targeted killing activity against the bacterium by promoting membrane permeability.