Structure–Activity Study of Antibacterial Poly(ester urethane)s with Uniform Distribution of Hydrophobic and Cationic Groups

Abstract

Infections associated with antibiotic-resistant bacteria have become a threat to the global public health. Antimicrobial polymers, which are synthetic mimics of antimicrobial peptides, have gained increasing attention, as they may have a lower chance of inducing resistance. The cationic−hydrophobic balance and distribution of cationic and hydrophobic moieties of these polymers is known to have a major effect on antimicrobial activity. We studied the properties of a series of facially amphiphilic antimicrobial surfactant-like poly(ester urethane)s with different hydrophobic pendant groups (P1, P2, and P3) and cationic groups distributed uniformly along the polymer chain. These polymers exhibited bactericidal activity against Gram-negative Escherichia coli and Pseudomonas aeruginosa, as well as Gram-positive Staphylococcus aureus and Staphylococcus epidermidis. Microscopy and dye release assays demonstrated that these polymers cause membrane disruption, which is dependent on the cationic−hydrophobic ratio in the polymer. Membrane permeability assays revealed that these polymers can permeabilize the outer membrane of E. coli and damage the cytoplasmic membrane of both E. coli and S. aureus. In addition, our results indicate that the three polymers exhibit a different extent of membrane disruption against E. coli. P1 caused minor damage to the cytoplasmic membrane integrity, but it was able to dissipate the cytoplasmic membrane potential, leading to cell death. P2 and P3 depolarized the cytoplasmic membrane and also caused significant damage to the cytoplasmic membrane. Overall, we showed a new class of broad-spectrum bactericidal polymers whose membrane disrupting ability against E. coli correlates with the structural differences of the hydrophobic pendant groups.

Peptidomimetic polyurethanes disrupt surface established bacterial biofilms and prevent biofilm formation

“…However, in a very clear trend, polymers with mArg caused significantly more hemolysis than their mLys counterparts, which corroborated our previous reports on a similar polyurethane platform. In accordance with multiple reports in the literature, 42,[59][60][61] the hemolysis was observed to be significantly higher for polymers with the more hydrophobic mPhe pendant group compared to the polymers with mAla, indicating that even with the same overall cationic charge, increasing hydrophobicity increases the hemolytic activity of the polymers.…”

“…Since these polymers share design features with antimicrobial polymers, we also evaluated their antimicrobial activity against planktonic bacteria using the modified broth microdilution method. [42][43][44] The MIC of the polymers was determined in MHB, LB, and BM2 minimal medium. As depicted in Table 2 the polymers showed no inhibitory activity against P. aeruginosa, S. aureus, or E. coli in MHB or LB until 250 μg/mL above which they could not be tested due to their poor solubility in LB and MHB.…”

“…25 We have previously reported a library of synthetic peptidomimetic antimicrobial polymers with tunable selectivity and low cytotoxicity. [42][43][44][45] In this study, we focused on variants of these polymers with activity against biofilms and systematically explored the mechanisms behind their antibiofilm characteristics through structureproperty relationships. Inspired by natural [31][32] and synthetic [33][34][35]46 antibiofilm peptides reported in the literature, we designed polyurethanes using our pendant-functionalized, amino acid mimetic monomer library to understand how individual amino acid mimetic units would influence the activity of the polyurethane against biofilms, and the surface interactions of bacteria preceding biofilm formation.…”

Poly(2‐Oxazoline)‐Based Functional Peptide Mimics: Eradicating MRSA Infections and Persisters while Alleviating Antimicrobial Resistance

“…This observation was different from the generally recognized antimicrobial mechanism of HDPs that enrich on the cell membrane from the outside and disrupt cell membrane integrity. [16] About 30 seconds after the polymer started enriching in cytoplasm, PI entered the cytoplasm,i ndicating damage to bacteria membrane,w hich was endorsed by the ortho view of Z-stack images confirming the colocalization of Dye-Gly-POX 20 with PI inside the bacteria (Figure 3b,c).…”

The function of peptide-mimetic anionic groups and salt bridges in the antimicrobial activity and conformation of cationic amphiphilic copolymers

“…Many efforts have been made to develop antimicrobial polymers based on different polymer backbones, such as methacrylate, 17,18 and optimize the monomer compositions and chemical identities of cationic and hydrophobic groups for potent antimicrobial activity and selectivity. [19][20][21] Recently, the approach has been extended to block copolymers with specic sequences, 22,23 branched polymers, [24][25][26] comb-like polymers, 27,28 polymer assemblies and micelles, 29,30 and single-chain polymer nanoparticles. [31][32][33] In addition, polymers with facially cationic amphiphilicity in the side chains have shown to promote effective interactions of the polymer with the bacterial cell membrane, causing subsequent membrane disruption.…”