Influence of the linkage between long alkyl tails and cationic groups on membrane activity of nano-sized hyperbranched polyquaterniums

[Display omitted] The recurrent emergence of serious pathogens necessitates novel insights and highly efficient antibacterial agents. However, the innate inability of metal ions and reactive oxygen species (ROS) to differentiate between bacteria and mammalian cells presents a challenge, limiting the selectivity crucial for an ideal antimicrobial solution. Herein, we present a systematic exploration involving two variants of nano-sized hyperbranched polyquaterniums (NHBPQs) - one featuring a lengthy alkyl tail linked to the ammonium unit at the N-atom center (NHBPQ-A), and the other in a segregated configuration (NHBPQ-B). The exterior alkyl chain chains act as a barrier to the cationic group's non-specific adsorption due to spatial site resistance, causing NHBPQ-A in broad-spectrum cytotoxicity. Conversely, the distinct molecular configuration of NHBPQ-B in the segregated state affords greater flexibility, allowing the cationic groups to be released and interact non-specifically, finally resulting in selective bactericidal activity. Leveraging this selectivity, the optimized NHBPQ-B exhibits robust anti-infectious performance in a model of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds. This work establishes a promising avenue for biocompatible NHBPQs, holding significant potential in addressing MRSA infections and ameliorating both genetically encoded and phenotypic antibiotic resistance mechanisms.