Bacterial infections and antibiotic resistance, particularly by Gram-negative pathogens, have become a global healthcare crisis. We report the design of a class of cationic antimicrobial polymers that cluster local facial amphiphilicity from repeating units to enhance interactions with bacterial membranes without requiring a globally conformational arrangement associated with highly unfavorable entropic loss. This concept of macromolecular architectures is demonstrated with a series of multicyclic natural product-based cationic polymers. We have shown that cholic acid derivatives with three charged head groups are more potent and selective than lithocholic and deoxycholic counterparts, particularly against Gram-negative bacteria. This is ascribed to the formation of true facial amphiphilicity with hydrophilic ion groups oriented on one face and hydrophobic multicyclic hydrocarbon structures on the opposite face. Such local facial amphiphilicity is clustered via a flexible macromolecular backbone in a concerted way when in contact with bacterial membranes.

New antimicrobial agents are needed to address ever-increasing antimicrobial resistance and a growing epidemic of infections caused by multidrug resistant pathogens. We design nanostructured antimicrobial copolymers containing multicyclic natural products that bear facial amphiphilicity. Bile acid based macromolecular architectures of these nanostructures can interact preferentially with bacterial membranes. Incorporation of polyethylene glycol into the copolymers not only improved the colloidal stability of nanostructures but also increased the biocompatibility. This study investigated the effects of facial amphiphilicity, polymer architectures, and self-assembled nanostructures on antimicrobial activity. Advanced nanostructures such as spheres, vesicles, and rod-shaped aggregates are formed in water from the facial amphiphilic cationic copolymers via supramolecular interactions. These aggregates were particularly interactive toward Gram-positive and Gram-negative bacterial cell membranes and showed low hemolysis against mammalian cells.

Amphiphilic molecules, including macromolecules and small surfactants, inherently self-assemble into a wide variety of nanostructures in selective solvents. However, the sequential structure for synthetic polymers is largely restricted to block copolymers. In this work, we report facial amphiphilicity-induced self-assembly (FAISA) of gradient amphiphilic copolymers. This new approach is demonstrated using facial amphiphilic multicyclic compounds. The facial amphiphilicity of bile acids allows cationic copolymers to form aggregates with different morphologies in aqueous solution. By tuning the compositions of hydrophilic and hydrophobic segments, these copolymers can self-assemble in water to produce spherical, vesicle, and rodlike nanostructures via supramolecular and electrostatic interactions. The hydrophobic interaction from multicyclic hydrocarbon moieties largely dictates the self-assembly process, which can be further modulated by integrating neutral hydrophilic poly(ethylene glycol) in copolymer compositions with additional stimuli such as temperature, charge density, and ionic screening.

Cobaltocenium‐containing polyelectrolyte block copolymer nanoparticles were prepared via polymerization‐induced self‐assembly (PISA) using aqueous dispersion RAFT polymerization. The cationic steric stabilizer was a macromolecular chain‐transfer agent (macro‐CTA) based on poly(2‐cobaltocenium amidoethyl methacrylate chloride) (PCoAEMACl), and the core‐forming block was poly(2‐hydroxypropyl methacrylate) (PHPMA). Stable cationic spherical nanoparticles were formed in aqueous solution with low dispersity without adding any salts. The chain extension of macro‐CTA with HPMA was efficient and fast. The effects of block copolymer compositions, solid content, charge density, and addition of salts were studied. It was found that the degree of polymerization of both the stabilizer PCoAEMACl and the core‐forming PHPMA had a strong influence on the size of nanoparticles. © 2019 Wiley Periodicals, Inc. J. Polym. Sci. 2020, 58, 77–83

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