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The findings from the investigation of an ensemble of amphiphilic polymers derived from 2-aminoethyl acrylate establish significant effects of variation in the topographical position of the cationic center and hydrophobic segments on their biological activities. For example, the isomeric polymer pair of poly(6-aminohexylacrylate) and poly(2-(butyla...
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... antibacterial activities of the polymers were determined in terms of minimum inhibitory concentration (MIC) against E. coli TOP 10 (ampicillin resistant) and S. aureus ATCC 25923 ( Fig. 1 and Table 1). Homopolymers with one to three carbon tails in the 6k g mol À1 series displayed high and similar activ- ities against Gram positive S. aureus (Fig. 1a, MIC ¼ 62 mg mL À1 ). However, this homopolymer series displayed much lower antibacterial activity towards E. coli than with S. aureus (Fig. 1a). With the addition of one ...
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... antibacterial activities of the polymers were determined in terms of minimum inhibitory concentration (MIC) against E. coli TOP 10 (ampicillin resistant) and S. aureus ATCC 25923 ( Fig. 1 and Table 1). Homopolymers with one to three carbon tails in the 6k g mol À1 series displayed high and similar activ- ities against Gram positive S. aureus (Fig. 1a, MIC ¼ 62 mg mL À1 ). However, this homopolymer series displayed much lower antibacterial activity towards E. coli than with S. aureus (Fig. 1a). With the addition of one more carbon to the three carbon tail, the homopolymer poly(N-butyl) showed a marked increase in biological activity towards both bacteria and RBCs. A conspicuous ...
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... resistant) and S. aureus ATCC 25923 ( Fig. 1 and Table 1). Homopolymers with one to three carbon tails in the 6k g mol À1 series displayed high and similar activ- ities against Gram positive S. aureus (Fig. 1a, MIC ¼ 62 mg mL À1 ). However, this homopolymer series displayed much lower antibacterial activity towards E. coli than with S. aureus (Fig. 1a). With the addition of one more carbon to the three carbon tail, the homopolymer poly(N-butyl) showed a marked increase in biological activity towards both bacteria and RBCs. A conspicuous surge in orders of magnitude of the biological activities was observed in going from homopolymers to copoly- mers. Random copolymer copoly(butyl)-6k ...
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... in biological activity towards both bacteria and RBCs. A conspicuous surge in orders of magnitude of the biological activities was observed in going from homopolymers to copoly- mers. Random copolymer copoly(butyl)-6k displayed high antibacterial activity against both S. aureus (MIC ¼ 34 mg mL À1 ) and E. coli (MIC ¼ 13 mg mL À1 ), as shown in Fig. 1c and Table 1. Similarly, the three copolymers with six-carbon alkane groups attached to the polymer backbone: copoly(linear)-6k, copoly(cyclo)-6k, and copoly(branched)-6k, displayed high activity against both S. aureus and E. coli ( Fig. 1c and Table 1). The role of the molecular weight of the homopolymers in their biological activity ...
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... activity against both S. aureus (MIC ¼ 34 mg mL À1 ) and E. coli (MIC ¼ 13 mg mL À1 ), as shown in Fig. 1c and Table 1. Similarly, the three copolymers with six-carbon alkane groups attached to the polymer backbone: copoly(linear)-6k, copoly(cyclo)-6k, and copoly(branched)-6k, displayed high activity against both S. aureus and E. coli ( Fig. 1c and Table 1). The role of the molecular weight of the homopolymers in their biological activity is apparent from Fig. 1 and Table 1. Smaller molecular weight homopolymers were inactive against E. coli (Fig. 1b), in contrast to the moderately active 6k g mol À1 series homopolymers. Similarly, the 1.6k g mol À1 series homopoly- mers, ...
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... Table 1. Similarly, the three copolymers with six-carbon alkane groups attached to the polymer backbone: copoly(linear)-6k, copoly(cyclo)-6k, and copoly(branched)-6k, displayed high activity against both S. aureus and E. coli ( Fig. 1c and Table 1). The role of the molecular weight of the homopolymers in their biological activity is apparent from Fig. 1 and Table 1. Smaller molecular weight homopolymers were inactive against E. coli (Fig. 1b), in contrast to the moderately active 6k g mol À1 series homopolymers. Similarly, the 1.6k g mol À1 series homopoly- mers, except poly(N-butyl)-1.6k, did not show activity against S. aureus, whereas the 6k g mol À1 series homopolymers ...
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... backbone: copoly(linear)-6k, copoly(cyclo)-6k, and copoly(branched)-6k, displayed high activity against both S. aureus and E. coli ( Fig. 1c and Table 1). The role of the molecular weight of the homopolymers in their biological activity is apparent from Fig. 1 and Table 1. Smaller molecular weight homopolymers were inactive against E. coli (Fig. 1b), in contrast to the moderately active 6k g mol À1 series homopolymers. Similarly, the 1.6k g mol À1 series homopoly- mers, except poly(N-butyl)-1.6k, did not show activity against S. aureus, whereas the 6k g mol À1 series homopolymers demonstrated high activity against S. aureus. The 1.6k g mol À1 series with low DP of $6 has a much ...
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... ascertain the toxicity of the polymers towards mammalian cells, the hemolytic activity (HC 50 ) of the polymers was measured against mouse RBCs. HC 50 is dened as the minimum concentration of a polymer solution required to cause lyses in 50% of RBCs within an incubation period of 1 h at 37 C. Our study found that all of our homopolymers, except poly(N-butyl), are non-hemolytic (HC 50 > 2000 mg mL À1 ), whereas copoly(butyl), the random copolymer, was highly hemolytic at both 6k g mol À1 and 1.6k g mol À1 molecular weight levels ( Fig. 1 & Table 1). Copoly(linear)-6k, copoly(cyclo)-6k, and copoly(branched)-6k displayed similar and high hemolytic activities despite having different shapes of hydrophobic side groups. ...
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Citations
... Common factors to regulate the selectivity of antimicrobial materials are for example the amphiphilic balance, 18-21 or the used type of cations. 19,[22][23][24][25] In addition, the polymer topology is an important factor which influences the properties of APs. ...
The one-pot synthesis of antimicrobial bottle brush copolymers is presented. RAFT polymerization is used for production of the polymeric backbone, as well as for the grafts, which were installed using a grafting from approach. A combination of N-iso propyl acrylamide and a Boc protected primary amine-containing acrylamide was used in different composition. After deprotection polymers featuring different charge densities were obtained in both, linear and bottle brush topology. Antimicrobial activity was tested against three clinically relevant bacteria strains and growth inhibition was significantly increased in bottle brush copolymers. Blood compatibility investigations revealed strong hemagglutination for linear copolymers and pronounced hemolysis for bottle brush copolymers. However, one bottle brush copolymer with a 50% charge density strong antibacterial activity and negligible blood toxicity resulting in selectivity values as high as 320. Membrane models were used to probe the mechanism of shown polymers, which was found to be based on membrane disruption. The trends from biology are accurately reflected in model systems indicating that differences in lipid composition are responsible for selectivity. However, bottle brush copolymers were found to possess increased cytotoxicity against HEK cells when compared with linear analogues. The introduced synthetic platform enables screening of further parameters associated to bottle brush copolymers, which might lead to even better activity profiles.
... The polymers are bilateral-on one side cationic residues act with the negatively charged bacterial cell-wall, on the other side hydrophobic domains interact with the lipophilic layers of the bacterial cell-wall leading to the disruption of the cell membrane [28,[139][140][141]. Many peptide-mimetic antibacterial polymers are already reported in the literature in recent decades, and are mainly derivatives of polymethacrylates [142,143], polyacrylates [144,145], polynorbornenes [146,147], poly(β-lactam)s [28,139], polymaleimides [148,149], and polycarbonates [150,151]. Extensive studies were dedicated to probing the correlation between antimicrobial activity and polymer amphiphilicity [143,152], structure (random or block) [136,153], type of cationic charge [154], molecular weight [145], and spaced arm (distance from polymer backbone to pendant cationic center) [1]. ...
... Many peptide-mimetic antibacterial polymers are already reported in the literature in recent decades, and are mainly derivatives of polymethacrylates [142,143], polyacrylates [144,145], polynorbornenes [146,147], poly(β-lactam)s [28,139], polymaleimides [148,149], and polycarbonates [150,151]. Extensive studies were dedicated to probing the correlation between antimicrobial activity and polymer amphiphilicity [143,152], structure (random or block) [136,153], type of cationic charge [154], molecular weight [145], and spaced arm (distance from polymer backbone to pendant cationic center) [1]. ...
Health-care systems that develop rapidly and efficiently may increase the lifespan of humans. Nevertheless, the older population is more fragile, and is at an increased risk of disease development. A concurrently growing number of surgeries and transplantations have caused antibiotics to be used much more frequently, and for much longer periods of time, which in turn increases microbial resistance. In 1945, Fleming warned against the abuse of antibiotics in his Nobel lecture: "The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant". After 70 years, we are witnessing the fulfilment of Fleming's prophecy, as more than 700,000 people die each year due to drug-resistant diseases. Naturally occurring antimicrobial peptides protect all living matter against bacteria, and now different peptidomimetic strategies to engineer innovative antibiotics are being developed to defend humans against bacterial infections.
... The balance between cationic residues (hydrophilicity) and hydrophobicity is a vital criterion in determining cell selectivity (bacterial cells vs mammalian cells) of these polymers. In recent years, the effects of various polymer attributes such as polymer amphiphilicity [12,18], polymer structure (random or block) [9,19], type of cationic charge [20][21][22][23], and polymer molecular weight [24] on the antimicrobial and hemolytic activities of synthetic polymers have been probed. Amphiphilic polyacrylates exhibiting antibacterial properties studied by several groups also exemplify the impact of structural design and composition on antibacterial and hemolytic activities [25][26][27][28][29]. ...
Synthetic polymers mimicking antimicrobial peptides (AMPs) in combating “superbugs” have received considerable attention in the genre of antimicrobial polymeric materials. Herein, we report the antibacterial and hemolytic activities of two series of random acrylate-based ternary copolymers with pendant hexamethylene ammonium, poly(oligoethylene glycol), and ethyl or N-methylethyl ammonium side chains. We have demonstrated that highly selective activity towards Escherichia coli (E. coli >68 times) and Bacillus subtilis (B. subtilis 400 times) compared to red blood cells can be achieved by controlling the structural composition of these copolymers via optimization of feed composition involving lipophilic units, cationic side-chain units, and neutral hydrophilic units. Furthermore, we have demonstrated a loss of viability for E. coli and B. subtilis following exposure to the copolymers using Fluorescence Lifetime Imaging Microscopy (FLIM), reinforcing the antibacterial efficacy of the synthesized ternary copolymers.
... Motivated by the excellent properties and promising applications of AMP nanoparticles, synthetic amphiphilic AMP-mimetic polymers are proposed [32][33][34]. These amphiphilic copolymers stimulate the structural features of AMPs, that is, cationic and hydrophobic moieties. ...
A novel series of amphiphilic mimicking antimicrobial peptide copolymers PCL16-b-Kn can assemble in water to form uniform vesicles. Transmission electron microscopy was used to observe the vesicular structure of the nanoparticles, and dynamic light scattering revealed their uniform size and narrow dispersion. Critical vesiculation concentrations were also tested, revealing that these vesicles can exist at low concentrations. Furthermore, in vitro and intracellular drug release of doxorubicin(DOX)-vesicles were conducted. These vesicles could encapsulate DOX and achieve efficient intracellular drug release. Overall, these copolymer vesicles exhibit potential application value as multifunctional drug-carrier systems with antibacterial capability in cancer therapy.
The correlation between the structure and biological activity of polymers is critically important for rationally designing effective antibacterial polymers. Here, the antibacterial activity, cytotoxicity, and selectivity of structurally well-defined, star-shaped...
Antibiotics resistance of bacteria has caused serious threats to public health and it is urgent to develop novel antibacterial agents that do not induce drug-resistance. Herein, a series of novel antibacterial copolymer PCL16-b-Kn mimicking the structure and action mechanism of natural antimicrobial peptides (AMPs) is reported. The diblock copolymers were synthesized via ring-opening polymerization and facile coupling reaction. The antibacterial results confirmed that the diblock copolymers possess superior antibacterial activities and rapid antibacterial speed against both S. aureus and E. coli. A conclusion can be drawn that the antibacterial activity can be promoted by achieving a balance between the cationic and hydrophobic segments in the copolymer. Further hemolysis and cytotoxicity tests suggest the excellent biocompatibility of these diblock copolymers. Overall, our synthetic strategy demonstrates a new thought of designing novel biocompatible antibacterial copolymers and expands the categories of next-generation antibacterial agents without inducing drug resistance.
The increasing prevalence of antibiotic-resistant bacterial infections, coupled with the decline in the number of new antibiotic drug approvals, has created a therapeutic gap that portends an emergent public health crisis. Since the 1980s, host defense peptides (HDPs) have been recognized as antibacterial compounds that do not induce resistance, but are hampered by their high cost and lack of synthetic scalability. Starting in the early 2000s, synthetic (co)polymers have been designed to mimic the salient physiochemical features of HDPs. These polymers have shown broad-spectrum antimicrobial activity, rapid bactericidal kinetics, and a very low propensity to induce resistance. Systematic optimization of the (co)polymer composition, chain length, hydrophobicity, and cationic charge has generated select examples that are also highly biocompatible (non-hemolytic and non-cytotoxic in vitro). These polymers are derived from inexpensive feedstocks and are produced using cost-effective, scalable processes. Accordingly, such polymers may be viewed as early stage pre-clinical candidates for potential use in pharmaceutical or therapeutic applications. In this review, we focus on the key macromolecular design principles that have been gleaned from more than a decade of structure–activity relationship (SAR) studies, as well as some key mechanistic investigations, across this multidisciplinary field. A fundamental understanding of these functional (co)polymers has arisen from a convergence of ideas in polymer chemistry, microbiology, and biophysics. In this context, we emphasize the recent advances from the past few years and emerging opportunities surrounding the rapidly growing field of HDP-mimetic antimicrobial polymers.
The global health threat of antimicrobial resistance has created a pressing need to develop practical alternatives to conventional antibiotic agents. Peptide mimetic synthetic amphiphilic polymers are known to non-specifically disrupt the bacterial cell surface thus leading to highly hindered bacterial resistance development. We investigated the antibacterial activities of a terpolymer macromolecular architecture with a combination of 6-carbon and 2-carbon spacer arms (distance from polymer backbone to pendent cationic center) interspersed with counits with hydrophobic side groups. A random copolymer with a combination of 6-carbon spacer arm repeat units (60 mol%) and 2-carbon spacer arm (40 mol%) units is moderately active against bacteria and shows very low hemolytic activity. Incorporation of comonomer units with alkyl side groups, by replacing different levels of 2-carbon spacer arm counit, led to substantial increments in antibacterial activities without detrimental effects on hemolytic activities leading to highly selective (bacteria over red blood cells) antibacterial activity. Time-kill studies revealed rapid bactericidal activity of the terpolymer against both Staphylococcus aureus and Escherichia coli with 100% killing efficiency achieved within 1 h of polymer treatment, corresponding to a 5-log reduction of bacterial colony forming units. These results indicate the high potential of this amphiphilic terpolymer architecture in the development of alternatives to antibiotics.
Antibacterial polymers that can selectively kill bacteria sparing the mammalian cells are still an unmet need. Here, we report cationic-amphiphilic polymers with variations in side chain architecture such as cyclization, isomerization and unsaturation that resulted in potent antibacterial activity and low mammalian cell toxicity with membrane-active mode of action.
