Bacterial infections pose a major global health concern, exacerbated by the overuse of antibiotics leading to the rise of bacterial resistance [[1], [2], [3]]. In response to this challenge, there has been considerable focus on the development of cationic antimicrobial materials [[4], [5], [6], [7], [8]]. These materials, inspired by biomimetic natural antimicrobial peptides, effectively disrupt the bacterial cell through electrostatic interaction with the negatively charged bacterial membrane. This approach not only offers unique antimicrobial benefits but also shows a lower propensity for resistance development. Nonetheless, the presence of cationic groups in these materials also pose toxicity risks to healthy cells and tissues, raising concerns for human health [[9], [10], [11]].
One commonly employed strategy to strike a delicate balance between antibacterial efficacy and cytotoxicity is the incorporation of pH-responsive functional groups into cationic polymer structures [[12], [13], [14]]. The pH-responsive cleavable functional groups, such as maleimide and Schiff base, are often employed as protective groups for cationic moieties [15,16]. In the bacterial infection-induced acidic conditions, these neutral or negatively charged groups undergo cleavage to transform to the cationic moieties, showcasing their antibacterial properties. However, once the responsive cleavage reaction occurs, it becomes irreversible, resulting in the continuous exposure of the cationic groups and rendering their cytotoxic effects uncontrollable. Another commonly used approach involves reversibly modulating the antibacterial activity of cationic polymers in different pH environments by leveraging the protonation degree of amine groups [17,18]. The synthesis of such materials usually requires meticulous design of monomers to precisely control the ratio of cationic amine units. The substantial complexity in synthesis significantly restricts the application of cationic antibacterial polymers.
Unlike conventional regulation mentioned above, protein conformational changes represent a precise and efficient biological regulatory mechanism [19,20]. In the case of ion channels, alterations in membrane potential can trigger conformational transitions in voltage-sensing elements, enabling the precise switching of functional regions between active and resting states (Scheme 1A) [21,22]. Inspired by voltage-gated ion channels, we hypothesize whether integrating cationic groups into proteins could enable precise regulation over the activation and silencing of antimicrobial function through protein secondary structure transitions. Such a strategy could potentially endow cationic polymers with intelligent antimicrobial capabilities, thereby mitigating the side effects associated with cationic moieties and significantly delaying the emergence of antibiotic resistance. Concanavalin A (ConA), one of the earliest well-characterized lectins, is then considered as an ideal protein model material [23]. With 24 acidic and 27 basic amino acid residues among its 237 amino acids, ConA exhibits natural pH-responsive characteristics with an isoelectric point around 6 [24]. Under neutral conditions, ConA is predominantly in a β-sheet configuration, displaying a strong negative charge. In acidic environments, a portion of the β-sheet conformation in ConA transforms into an α-helix, accompanied by a shift in surface potential to near neutrality [25,26]. The reversible conformational changes in ConA enable controlled reversal of its charge under different pH environments, holding promise for intelligent modulation of cationic moieties [17,27,28]. Of particular interest, ConA possesses specific recognition sites, enabling precise construction of protein–cationic polymer conjugates through lectin–carbohydrate interactions [[29], [30], [31]], thus simplifying the synthesis process and broadening the potential applications of such materials.
An antibacterial polysulfonium with high cytotoxicity was subsequently selected as the model cationic polymer material to validate the feasibility of our biomimetic strategy (Table 1). Mannose moieties were modified at both ends of the polymer without affecting its biological activity. By employing isothermal titration calorimetry (ITC) to study lectin-carbohydrate specific interactions, we achieved precise structural control of ConA-polysulfonium nanoparticles (NPs). This was accomplished by enabling the cationic polysulfonium to interact exclusively through the mannose end groups with the specific recognition sites on the protein (Scheme 1B). Under neutral physiological conditions, the polysulfonium chains within the NPs exhibited extensive entanglement with ConA, resulting in the shielding of cationic functionalities and thereby reducing antibacterial activity and cytotoxicity. Conversely, the acidic microenvironment induced by bacterial infection triggered a secondary structure transformation in ConA, causing the cationic polymer chains to disentangle and distribute peripherally on the particles (Scheme 1A). This immediate conformational change activated the antibacterial functionality. The activated ConA–polysulfonium NPs demonstrated outstanding efficacy in eradicating Gram-positive bacteria (Staphylococcus aureus), Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia. coli), and fungal (Canidia. albicans) biofilms, as well as remarkable therapeutic effects in a murine acute pulmonary infection model. By employing a biomimetic design inspired by voltage-gated ion channels, we demonstrated that the exposure and shielding of cationic moieties could be controlled through pH-induced secondary structure transitions in proteins. This biomimetic strategy eliminates the need for intricate and cumbersome synthesis processes. Leveraging the precise biological control mechanisms of proteins, it imparts antibacterial intelligence to polymers, mitigating the side effects associated with cationic moieties and significantly delaying the development of drug resistance.
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