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Materials Today: Proceedings 5 (2018) 17156–17161 www.materialstoday.com/proceedings

AMPCO-2017

Antibacterial Polymers – A Mini Review

Ankita Arora, Abhijit Mishraa*
a
Materials Science and Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat, 382355, India

Abstract

Multidrug resistance of pathogenic bacteria is a major health concern. Deterioration in the discovery of novel
antibiotics exacerbates the situation even further. Antimicrobial polymers could have a significant role in this global
effort to fight back this problem. This review paper focuses on the recent advances in the synthesis of membrane-
active antimicrobial polymers, their classification and mode of action. Amphiphilic antimicrobial polymers, which
are synthetic mimics of antimicrobial peptides, have received much attention as they have lower susceptibility for
developing resistance than other small molecular antibiotics. In addition, control over their structural parameters –
like hydrophobicity/ hydrophilicity balance, cationicity, molecular weight, functional groups, degree of
polymerization, chain length – may enhance their antimicrobial activities while minimizing toxicity to mammalian
cells.

© 2018 Elsevier Ltd. All rights reserved.

Selection and/or Peer-review under responsibility of Advances in Materials & Processing: Challenges & Opportunities (AMPCO-2017).

Keywords: antimicrobial polymers; synthetic mimic; antibiotic resistance; antimicrobial peptides

1. Introduction

The emergence of multidrug-resistant pathogens towards conventional antibiotics has urged the need of novel
antimicrobial agents [1]. This has become one of the biggest threats to the healthcare system worldwide. According
to World Health Organization the consequence of these multidrug resistance pathogens is global where microbial
infection once again could become the main cause of death. The failure to address this problem could result in 10
million deaths by 2050 [2]. In this alarming situation we urgently need new antimicrobial agents that allow us to
handle this problem. The challenge lies in trying to develop antimicrobial polymers with well-tolerated antimicrobial
efficacy and low cytotoxicity.

* Corresponding author. E-mail address: amishra@iitgn.ac.in

2214-7853 © 2018 Elsevier Ltd. All rights reserved.

Selection and/or Peer-review under responsibility of Advances in Materials & Processing: Challenges & Opportunities (AMPCO-2017).
 Arora et al. / Materials Today: Proceedings 5 (2018) 17156–17161 17157

In the past few years, the large class of antimicrobial macromolecular systems, polymers, and copolymers, either
quaternized or functionalized with bioactive groups, have been rigorously developed, and effectively used as
antimicrobial agents. Along with these, new moderately hydrophobic polymer structures have also been synthesized,
which contain protonated primary or secondary/tertiary amine groups that displayed relatively higher antimicrobial
activity, often unlike their quaternary analogues [3]. The antimicrobial polymers are classified on the basis of their
mode of action as passive and active. Passive polymers prevent the growth of the microbes by minimizing their
adhesion to surfaces. Examples include Poly(ethylene glycol), Poly(sulfobetaine methacrylate), polyphenols, poly
(dimethyl acrylamide) etc. Active polymers, on the other hand, either interact with the cell wall of microbes and
disrupt their cytoplasmic membrane, or interfere with key intracellular processes of the microbe [4–7]. Nisin-
immobilized organosilicon, polyurethane containing quaternary ammonium, poly(n,n-diethylethylene diamine-co-
yrosol-based acrylic), organosilicon quaternary ammonium chloride and poly(2-(dimethylamino)ethyl methacrylate)
tethering quaternary ammonium are some examples of active polymers [8–11]. Other features associated with these
antimicrobial polymers for a better efficacy are cationicity, amphipathic nature, hydrophobic functional group,
molecular weight, degree of polymerization, activity against a wide variety of microbes and toxicity to host cells
[12–14]. This review briefly highlights and summarizes the results of studies during the recent years, which concern
the mechanism of action of different antimicrobial polymers and synthetic mimics of AMPs, factors influencing their
activity and toxicity, as well as major applications of antimicrobial polymers.

2. Polymeric antibiotics

Broadly categorized antimicrobial polymers are passive and active where the passive polymer layer prevents the
adhesion of bacteria by decreasing the protein adsorption on its surface, thereby repelling the bacteria without
actively interacting with it. As microbes have mainly hydrophobic and negatively-charged properties, passive
polymers should be either (1) hydrophilic; (2) negatively-charged; or (3) have a low surface free energy [15,16].
Therefore typical passive polymers comprise (1) self-healing, slippery liquid-infused porous surface (SLIPS), such
as poly(dimethyl siloxane); (2) uncharged polymers, such as poly(ethylene glycol) (PEG), poly(2-methyl-2-
oxazoline), polypeptoid, polypoly(n-vinyl-pyrrolidone), and poly(dimethyl acrylamide); and (3) charged
polyampholytes and zwitterionic polymers, such as phosphobetaine, sulfobetaine, and phospholipid polymers
[17,18].

On the other hand active polymers actively kill bacteria when their surface is functionalized with active agents,
like cationic biocides, antimicrobial peptides or antibiotics. The mechanism of action of active polymers depends on
the activity of functionalized group present on it. For instance the most widely used is positively-charged quaternary
ammonium which interacts with the cell wall and damages the cytoplasmic membrane, resulting in the leakage of
intracellular components and consequent cell death [19]. Some other examples are polyethylenimine, polyguanidine,
and N-halamine. Polyethylenimine puncture the bacterial plasma membrane by the electrostatic interaction between
polyethylenimine and the plasma membrane. Polyguanidine disrupts the Ca2+ salt bridges which inhibits the bacterial
growth and subsequent cell death. N-halamine inhibits or inactivates the cell by action of oxidative halogen targeted
at thio or amino groups of cell receptors [20].

The polymers can also be tuned to possess antimicrobial activity by attaching some active groups to it. On the
basis of attachment of these active groups these are classified as polymeric biocides and biocidal polymers.
Polymeric biocides covalently attach the bioactive repeating units with antimicrobial activity such as amino,
carboxyl and hydroxyl groups [15,21,22]. The polymerization process may either increase or decrease the
antimicrobial activity of bioactive functional groups. Some of the examples of polymeric biocides are sulfonium salt,
quaternary ammonium, benzimidazole, halogen and N-halamine [19,23–25]. On contrary the biocidal polymers do
not require any bioactive repeating units, instead the antimicrobial site is represented by the entire macromolecule.
Many biocidal polymers comprise of cationic biocides, such as quaternary ammonium, phosphonium, tertiary
sulfonium, and Guanidinium [26,27]. Microbes generally have a negative charge on their plasma membrane.
Cationic polymers can lead to the destabilization of the cell surface and eventually induces bacterial death [28].
17158 Arora et al. / Materials Today: Proceedings 5 (2018) 17156–17161

2.1. Features of polymeric antibiotics

The cidal activity of antimicrobial polymers are tested against wide variety of bacteria that includes gram
positive, gram negative and other multi drug resistant bacteria by studying their MIC90 which is minimum inhibitory
concentration at which 90% of bacterial cell growth is inhibited. The relationship between the antimicrobial activity
and molecular weight (MW) of the polymer has been reported by many researchers [12,13,29]. Some have revealed
a parabolic dependence of MW on the antimicrobial properties of the synthesized quaternary ammonium
functionalized poly(propyleneimine) dendrimers [30], while some synthesized a series of different oligomeric
guanidines and showed that lower MWs result in a rapid decrease in activity [31]. Some quaternized and alkylated
common polymers like N-hexyl-PVP and N-hexyl, N-methyl PEI, in immobilized state, requires a minimal polymer
size to employ full bactericidal effect [32–34]. Several research groups have synthesized low molecular weight
antimicrobial oligomers [35–38]. Researchers have synthesized polynorbornene derivatives by ring-opening
metathesis polymerization (ROMP) and used a design rule to vary the amphiphilic moiety to adjust the antimicrobial
and hemolytic behavior [39,40]. Mowery et al. synthesized statistical copolymers of β-lactams to design an
amphipathic, antimicrobial polymer [41]. Antimicrobial polyethylene glycol (PEG) functionalized polymers from
methacrylate derivatives are synthesized by RAFT polymerization to further enhance the biocompatibility of
antimicrobial polymers [42]. It is understood that there is a correlation between the chain length and chemical group
to antimicrobial properties, for instance best antimicrobial properties are exhibited by polymers of shorter
hydrophobic chain lengths. DeGrado and Kuroda prepared antimicrobial poly- (methacrylate) derivatives via free
radical polymerization and it is concluded that primary amines helped to increase antimicrobial properties, on the
other hand polymers having quaternary ammonium structure required the additional hydrophobic functionality to be
potent. Thus for antimicrobial polymers the hydrophobicity is a driving force for its microbicidal activity, though the
excess of the same causes hemolytic activity. The hydrophobicity increases from methyl to propyl with an increase
in antimicrobial activity but if it further increases from propyl to hexyl, the antimicrobial activity decreases with a
drastic increase in the hemolysis. If the proportion of the hydrophobic group is enhanced, it also leads to increased
hemolytic as well as antimicrobial activities [40]. These attempts led to the fundamental design rule that the
cationic−hydrophobic ratio of the polymers must be optimized to amplify their antimicrobial activity and minimize
hemolytic activity. The cationic homopolymers with no hydrophobic side chains are likely to selectively bind to
anionic bacterial cell membranes over zwitterionic human cell membranes by electrostatic interactions, but not
capable of dividing(inserting) into and subsequently rupturing the membranes. However, if the overall copolymer
hydrophobicity is too high, hemolysis occurs through nonspecific binding to all membranes including host cells,
driven by hydrophobic interactions. Hence, the optimal monomer composition for potent antimicrobial activity with
bacterial selectivity is the stabilizing point between the capability of polymers to rupture membranes by hydrophobic
interactions and the selective binding to bacteria by electrostatic interactions [41]. These are all important attributes
for polymeric antibiotics that hope to successfully tackle resistance in the future.

3. Synthetic mimics of AMPs

Lately, there has been an increasing interest in the synthetic mimics of the antimicrobial peptides (SMAPs)
involving synthesis of novel polymer mimics and exploration of mechanism of their antimicrobial action [14,35].
Therefore the focus has now shifted to methods that allow chemists to synthetically capture the vital characteristics
of AMPs within a synthetic polymer construct. This has encouraged the development of a wide variety of synthetic
AMP mimics based around various polymer backbones including polyvinylpyridines [43], polyanilines [44],
polycarbodiimides [45], polynorbornenes [39], nylon-3 copolymers [46], and polymethacrylates [27,47]. AMPs are
rich in arginine, lysine and tryptophan which are cationic and hydrophobic residues responsible for the antimicrobial
activity. Therefore researchers have synthesized 2-guanidinyl methacrylate (GEMA) as arginine mimic, 2- amino
ethyl methacrylate (AEMA) as lysine mimic and 2-(1H-indol-3-yl)ethyl methacrylate (IEMA) as tryptophan mimic.
Copolymers with arginine and tryptophan mimic (GEMA-co-IEMA) and lysine and tryptophan mimic (AEMA-co-
IEMA) are studied. It is reported that with increase in indole (tryptophan mimicking polymer) content, the
antimicrobial activity against wide variety of bacteria decreases and toxicity to host cell increases in both the
 Arora et al. / Materials Today: Proceedings 5 (2018) 17156–17161 17159

copolymers. Therefore it is critical to maintain an optimum balance between the cationicity and hydrophobicity to
achieve maximum activity and least toxicity [48].

However there are several other parameters considered to affect the efficacy of AMP mimics. First, lower
molecular weight polymers, similar to natural AMPs show greater antimicrobial activity than polymers with high
molecular weight. Low molecular weights polymers are aimed for the AMP mimics to eliminate the requirement for
biodegradation of polymers in the body, as these short oligomers are thrown out from the body by the renal system
[49]. Second, a precise amphipathic balance is required to incorporate both antibacterial activity and selectivity,
where activity is defined as toxicity to bacteria and selectivity is defined as toxicity to bacterial cells with limited
toxicity to mammalian cells. It has also been observed that increasing the hydrophobicity, through copolymerization
of cationic monomers with hydrophobic monomers of alkyl tails of different chain lengths, generally resulted in
increased antibacterial activity but at the expense of selectivity. Therefore it’s critical to maintain the cationic and
amphipathic properties of the polymer with high potency and low toxicity [50]. Advantages of synthetic
antimicrobial polymers include scalability, cost-effectiveness, and chemical stability in the biological milieu (i.e.,
they are not subject to rapid proteolytic degradation in vivo) [51].

3.1 Lysine arginine mimicking polymers

Naturally occurring AMPs display the ability to destroy a wide variety of bacteria, without toxicity to the host
eukaryotic cells due to preferable charge interactions between the dense population of negatively charged lipids on
bacterial cell surfaces and the cationic side chains of the peptide [52,53], similar cationic functionality is
incorporated into the polymer framework to improve selectivity. A wide number of AMP-mimicking synthetic
polymers have been synthesized by several research groups [39,46,54,55]. Such polymers have advantages over
peptides as they are typically inexpensive to manufacture on large scale, easier to produce and manipulate
chemically, as well as being more flexible to integrate into drug delivery systems and medical devices [56].

Synthetic polymers containing moieties mimicking lysine and arginine components found in AMPs have been
reported to show effectiveness against gram positive as well as gram negative bacteria, with the mechanism of
activity depends on the nature of the amino acid mimic. In order to incorporate the antimicrobial activity of both
lysine and arginine into a single water-soluble copolymer, a series of copolymers consisting lysine mimicking
aminopropyl methacrylamide (APMA) and arginine mimicking guanadinopropyl methacrylamide (GPMA) are
prepared via aqueous RAFT polymerization. Copolymers are prepared with varying ratios of the comonomers, with
varying degree of polymerization and narrow molecular weight distribution to simulate naturally occurring AMPs
[50].

For arginine mimicking polymer having guanidium moiety Gabriel et al., reported that substituting guanidinium
on polynorbornene backbone for primary amines improved selectivity without affecting the antimicrobial activity
[54]. Locock et al., using a methacrylate backbone, reported that guanidinium improved both activity and selectivity
[27]. These outcomes suggest the likelihood of expanding antimicrobial properties of synthetic systems by
integrating both lysine and arginine mimics in a single polymer [50]. However it seems to maintain a balance
between charge density, hydrophobic character and polymer length which needs to be regulated in order to
selectively optimize the antibacterial activity, cytotoxicity, hemolysis, and hemagglutination behavior as any
imbalance will cost either low activity or high toxicity. Nevertheless, the lysine and arginine mimicking synthetic
systems represent a new class of antimicrobial polymers for broad spectrum antibiotic development.

4. Conclusion

Microbial infections cause millions of deaths worldwide and affect a broad range of human activities. This
alarming situation of drug resistance is expected to get worse during the coming years due to several reasons such as
inappropriate prescription of antibiotics, incomplete patient treatment routines and the massive use of antibiotics in
17160 Arora et al. / Materials Today: Proceedings 5 (2018) 17156–17161

livestock feedstuff. Antimicrobial polymers played a key role to eliminate the consequences of this problem. These
substantial developments have widened the scope for the synthesis of polymers with strict control over the structure,
morphology and topology. It is possible to design and synthesize specific macromolecules with enhanced selectivity
and antibacterial activity. Another promising area involves synthetic mimics of AMPs that can mimic the host
defense peptides against which the resistance is harder to achieve. By tuning certain critical features like
amphipathicity, cationicity, molecular weight, chain length and functional group, it’s easy to synthesize a potent
AMP mimicking polymer with no cytotoxicity to mammals. This class of synthetic polymers is inexpensive and easy
to prepare, allowing the production of antimicrobial materials on industrial scales. Therefore, with these efficient
antimicrobial polymers it seems we can again develop a healthy environment.

Acknowledgements

We thank the DST (grant SB/FT/LS-216/2012) and IIT Gandhinagar for support.

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