Macromolecular-clustered facial amphiphilic antimicrobials

Abstract

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.

Fig. 1

Modes of action adopted upon approaching to a biomembrane surface. a Host-defense peptides adopting a globally amphiphilic helical conformation; b Synthetic antimicrobial polymers adopting a globally amphiphilic conformation; and c A flexible macromolecular chain clustering intrinsic local facial amphiphiles (this work). Red color: cationic/hydrophilic groups, yellow color: hydrophobic groups

Fig. 2

Design principle of cationic polymers with an intrinsic facial amphiphilic structure at repeat units. The key building block should have a multicyclic structure with the possibility for derivatization to possess one face hydrophilic and the other face hydrophobic. Cholic acid is illustrated as an example here

Fig. 3

Synthesis of cholic acid-containing polymers. Cholic acid (CA) converted into (2-methacryloyloxy)ethyl cholate (MAECA); RAFT polymerization of MAECA; post-polymerization modification with bromoalkanoyl chloride; quaternization with trimethyl amine

Fig. 4

Multicyclic natural product-based cationic polymer structures and their illustration. a, d CA polymer, b, e DCA polymer, c, f LCA polymer

Fig. 5

Cholic acid-based cationic polymers with different spacers. Chemical structures of polymers and their illustration

Fig. 6

Drug resistance study of CA_19k_5 against P. aeruginosa and E. coli upon multiple sublethal dose treatment. The Data are collected from the three replicates and the error bars represent the s.d. of three replicates

Fig. 7

CLSM and SEM images of E. coli and P. aeruginosa under control and CA_19k_5 treatment with two times of MIC concentration. Bacteria concentrations were 1.0 × 10⁶ CFU/mL. Bacterial solutions without CA_19k_5 were used as the control. Scale bar in confocal images is 25 µm and scale bar in SEM images is 2 µm

Fig. 8

A proposed mechanism of action of cholic acid-based polymers on the bacterial cell membrane: 1 diffusion, 2 surface binding, 3 membrane insertion and 4 membrane disruption. The illustrated cholic acid can be replaced by other multicyclic compounds that are modified with facial amphiphilicity