Antimicrobial cationic polymers: from structural design to functional control
Antimicrobial cationic polymers: from structural design to functional control
Antimicrobial cationic polymers mainly contain two functional components: the cationic groups and the hydrophobic groups. The antimicrobial activity is influenced by the type, amount, location and distribution of these two components. This review summarizes the designs and syntheses of antimicrobial cationic polymers by controlling the above two factors. It involves the structural designs from primary to secondary structures, from covalent to noncovalent syntheses and from bulk to surface. Furthermore, it will discuss how to advance structural designs toward functional controls for optimizing the antimicrobial performances and biocompatibility of antimicrobial cationic polymers. It is anticipated that this review will provide some guidelines for developing molecular engineering of antimicrobial cationic polymers with tailor-made structures and functions. Polymer Journal (2018) 50, 33-44; doi:10.1038/pj.2017.72; published online 1 November 2017
Antimicrobial polymer is one of the important research orientations in
polymer science for treatments with infectious diseases caused by
pathogenic microbes.1 So far, many different types of antimicrobial
polymers have been devised,2?7 including antimicrobial cationic
polymers,8,9 biocide-released polymers10,11 and so forth. Among them,
antimicrobial cationic polymers have attracted most of the attentions
in this field, because compared with antibiotics, antimicrobial cationic
polymers may not induce serious microbial drug resistance. Owing to
this feature, lots of efforts have been devoted to promote their
Antimicrobial cationic polymers mainly consist of two functional
components: one is the cationic groups and the other is the
hydrophobic groups. An overall picture of their antimicrobial
mechanism is that antimicrobial cationic polymers can be primarily
adsorbed onto the membrane of pathogenic microbes with the aid of
their cationic groups; then the hydrophobic groups mainly insert into
the membrane and disrupt it, thus leading to the death of pathogenic
microbes.12 Therefore, these cationic and hydrophobic parts are both
essential for the antimicrobial performances of antimicrobial cationic
In general, the primary and secondary structural designs have a
crucial role in fabricating antimicrobial cationic polymers. As for the
primary structural design, improving their antimicrobial activity to
pathogenic microbes and reducing their hemolytic effect are two main
aspects that need to be considered. In addition, devising the secondary
structures of antimicrobial cationic polymers based on ?-helical and
induced globally amphiphilic conformations can adjust the spatial
distribution of the cationic and hydrophobic groups, thus probably
benefiting to increase the antimicrobial activity.
Recently, host?guest systems constructed by antimicrobial cationic
polymers and water-soluble macrocycles have been developed,13 which
are highlighted by the following two features. One is to regulate the
antimicrobial activity of antimicrobial cationic polymers. The other is
to selectively differentiate Gram-positive and Gram-negative bacteria
and fungi. This host?guest strategy can be applied to a variety of
antimicrobial cationic polymers, thus providing new opportunities for
constructing smart antimicrobial materials.
This review aims to summarize different levels in fabricating
antimicrobial cationic polymers (Scheme 1). It will include their
designs of primary and secondary structures and discuss the
relationship between their structures and antimicrobial activity. By marrying
supramolecular chemistry to antimicrobial cationic polymers, we will
further highlight how to fabricate dynamic, reversible and adaptive
antimicrobial materials. It is highly anticipated that this review will be
helpful for the structural design and functional control of
antimicrobial cationic polymers.
PRIMARY STRUCTURAL DESIGNS OF ANTIMICROBIAL
Antimicrobial cationic polymers should contain two functional
components,12 the cationic groups and the hydrophobic groups. The
above two functional components can be connected in enormous ways
for constructing various antimicrobial cationic polymers with tunable
antimicrobial activity. Herein, we discuss different kinds of cationic
and hydrophobic groups and analyze the key factors in monomer
designs. In addition, the topological designs of antimicrobial cationic
polymers are discussed. It is hoped that the primary structural designs
will be helpful for establishing the fundamentals of molecular
engineering of antimicrobial cationic polymers.
Scheme 1 Schematic representations of different levels of structural designs for fabricating antimicrobial cationic polymers from primary to secondary
structures, from covalent to noncovalent syntheses and from bulk to surface.
Primary structural design of antimicrobial cationic polymers starts
with the rational devisal of monomers. To enrich the polymer on the
surface of microbial membranes and then to penetrate into their lipid
bilayer,7 two necessary components need to be contained in a
monomer, the cationic and the hydrophobic groups.
Cationic groups. Cationic groups are the ones that facilitate the
adsorption of antimicrobial cationic polymers to the surface of
microbial membranes. There are several choices that bear the cationic
centers, including ammonium ions,14?17 sulfonium ions,18
phosphonium ions19,20 and so forth. This section mainly focuses on
ammonium-based and iminium-based cationic groups because of
their simple syntheses and broad usages.
Ammonium groups. Cationic primary, secondary, tertiary and
quaternary ammonium groups are commonly regarded as one of
the common cationic groups in antimicrobial cationic polymers. The
antimicrobial cationic polymers bearing quaternary ammonium
groups have intrinsic positive charges without pH-dependence, while
the primary, secondary and tertiary ammonium groups of the
polymers can be only obtained by protonation of their corresponding
amines. It is noteworthy that the polymers bearing primary, secondary
or tertiary ammonium groups usually exhibit relatively high
antimicrobial potency and low hemolytic activity, compared with that
containing quaternary ammonium groups. Inspired by the natural
host defense peptides, Kuroda et al.21 investigated the bactericidal and
hemolytic activity of polymers with primary, tertiary amine groups
and quaternary ammonium groups, respectively. It is shown that
copolymers bearing primary and tertiary amine groups can be
modulated to have potent bactericidal activity while minimizing the
hemolysis. In this system, this kind of copolymers with primary amine
groups presented greatest antimicrobial activity (Escherichia coli) and
selectivity over red blood cells (RBCs). By manipulating the
component of antimicrobial cationic polymers, maximum value of hemolytic
activity/minimum inhibitory concentrations (HC50/MIC) was
obtained (4125) with 16 ?g ml ? 1 MIC value. Therefore, the low
hemolysis and high bactericidal activity can be achieved in one system,
which are important in medical applications.
Iminium groups. Apart from the ammonium groups, the iminium
structures are another common form of the cationic groups, like
pyridinium,22?25 imidazolium26,27 and guanidinium salts.28,29 The
difference between ammonium and iminium groups is that
the positive charges of the latter ones are delocalized evenly through
the ? bonds or aromatic conjugated systems, which may influence
their adsorptive ability to membrane. For example, Yang and
coworkers investigated the antimicrobial activity of polymers bearing
different iminium groups (pyridinium and imidazolium groups) and
quaternary ammonium group (Table 1).30 It is revealed that
iminiumcontaining cationic polymers have relatively low MICs against various
bacteria and fungus, compared with the analogs of quaternary
ammonium groups. The MICs were obtained after 18 h incubation
under 37 ?C. Therefore, the delocalization of the positively charges on
the iminium groups could be regarded as a beneficial factor for
enhancing the antimicrobial performances.
Hydrophobic groups. After adsorbed to the surface of microbial
membranes, the hydrophobic groups of antimicrobial cationic
polymers can insert into the lipid bilayer of microbial membranes and
disrupt it. This can cause the cytoplasm leakage, thus leading to the
cell death of microbes.31 In general, the hydrophobic groups are
usually used to penetrate into the membrane and their length and
types need to be considered in the monomer design.
Chain length of hydrophobic groups. For most of the effective
antimicrobial cationic polymers, the hydrophobic groups are mainly
hydrophobic alkyl chains, and their chain lengths often affect the
antimicrobial activity of the polymers. For instance, Hedrick and
coworkers designed a series of polycarbonates with different lengths of
alkyl chains between the quaternary ammonium moiety and the
polymer backbone, then studied their antimicrobial activity.32 As
shown in Table 2, their MICs against various pathogenic microbes
decrease as the spacer chain length grows from 3 to 8. Because within
a certain range, lengthening the chain can result in a more
hydrophobic structure that can more strongly interact with the lipid bilayer
of microbial membranes, thus increasing the antimicrobial activity.
Some antimicrobial cationic polymers even present high value of
HC50/MIC over 250 with good selectivity against Staphylococcus
aureus. Such effect can be also confirmed by many other research
groups based on various systems.15,33 It should be pointed out that
excessively increasing the chain length can bring about two
disadvantages. One is that superabundant hydrophobic structures may lead to
intense aggregation between the polymers, thus weakening their
biocidal activity. The other one is that such structures could result
in increased hemolytic activity. Therefore, an appropriate chain length
of the hydrophobic group should be optimized.
Types of hydrophobic groups. A majority of antimicrobial cationic
polymers use linear alkyl groups as their hydrophobic groups.
Abbreviation: MIC, minimum inhibitory concentration.
Adapted with permission from ref. 30. Copyright 2014 American Chemical Society.
Besides that, cyclic or fused cyclic structures can be also utilized.
To investigate how the cyclic hydrophobic groups influence the
antimicrobial activity, Gellman and co-workers synthesized two
kinds of nylon-3 random copolymers with cyclohexane groups or
analogs acyclic groups (Figure 1a).34 The polymers with cyclohexane
groups show higher antimicrobial activity and weaker hemolytic
effect than the ones carrying similar acyclic groups. In addition,
Decho and co-workers connected derivatives of resin acids to the
poly(?-caprolactone) as hydrophobic groups (Figure 1b).35 This
kind of polymers, containing resin ring structures, exhibit
considerable antimicrobial activities against a broad spectrum of
bacteria (MICs: Gram-positive bacteria 0.7?10.1 ?M; Gram-negative
bacteria 3?40 ?M) with high selectivity (HC50 even higher than
860 ?M). From the experiments, they suggested that the great
antimicrobial activity was related to the structure of resin acids and
hydrophobicity. Therefore, cyclic hydrophobic groups are potential
candidates for fabricating antimicrobial cationic polymers with high
The topology of polymers determines the way that its monomer
structures are placed along the chain. Different spatial distributions of
these functional groups will generate different forms of hydrophobic
and hydrophilic regions deploying in the polymer, which could exert
influences to the bioactivity of an antimicrobial agent. For this
concern, plenty of methods have been developed for regulating
the topological structure of a polymeric antimicrobial. Owing to
well-established polymerization methods, a variety of antimicrobial
cationic polymers with different topological structures can be easily
Main-chain cationic polymers. Main-chain cationic polymers refer to
linear polymers bearing cationic centers along the macromolecular
chains, which can be usually synthesized by the intermolecular
condensation or the self-condensation of monomers.36 In a
mainchain cationic polymer, the multiple cationic centers are densely
deployed in the polymeric backbone, which can enhance the
adsorption of the polymer to the surface of microbial membranes. Moreover,
the molecular weights of the main-chain cationic polymers prepared
in these ways are not very high due to the limitation of the synthetic
methods, For example, Zhang and co-workers synthesized an
imidazolium-containing antimicrobial polymer and evaluated its
bactericidal activity and biocompatibility (Figure 2).37 This
mainchain cationic polymer can greatly inhibit the growth of most
pathogenic bacteria. Interestingly, this kind of polymer with relative
low degree of polymerization shows almost non-hemolytic effect
towards RBCs. For example, its HC50/MIC value against
methicillinresistant S. aureus is higher than 3000, which was obtained after 24 h
incubation under 37 ?C. Because of their relatively low molecular
weights, the main-chain cationic polymers can fill the gap between
small molecular antimicrobials and long-chain antimicrobial cationic
In addition, Cakmak et al.38 utilized benzyl amine and
epichlorhydrin to synthesize a series of polyelectrolytes with various molecular
weights and evaluated their antimicrobial activity against bacteria,
yeast and fungi. It is suggested that longer polymer chains and higher
density of positive charges could impose more considerable inhibition
on the growth of the bacteria and yeast with MICs 2.5 and
0.625 ?g ml ? 1, respectively. On the basis of different synthetic
methods, the number of positive charges, spacer length and
molecular weight could be readily tuned to be more practical in real
Following the application of ring-opening polymerization, a new
kind of antimicrobial polycarbonate hydrogels with broad spectrum
was constructed.39 This kind of antimicrobial polycarbonate hydrogels
can be rapidly biodegraded in 4 to 6 days, and present excellent ability
to kill Gram-negative bacteria, Gram-positive bacteria and even fungi
with 99.999% kill efficiency after 18 h incubation at 37 ?C. The
microbial inhibition prerequisite of antimicrobial hydrogel is directly
contacting on the surface, and the hydrogels present non-hemolytic to
RBCs after 1 h incubation. Therefore, the development of the
antimicrobial hydrogels can be well utilized in implantable and
Side-chain cationic polymers. Different from the main-chain cationic
polymers, there are a series of side-chain cationic polymers, which can
be used as antimicrobials. Side-chain cationic polymers can be
fabricated by many methods of living polymerization.40,41 Therefore,
their molecular weight and molecular weight distribution can be
finetuned. In addition to the homopolymers, the random, alternating and
block copolymers can be prepared in a designed manner.42,43 Thus,
the spatial distributions of cationic centers and hydrophobic groups
are able to be rationally adjusted.
Yoon and co-workers prepared block copolymers of
polystyrene-bpoly(4-vinyl pyridine) and random copolymers of
poly(styrene-r-4vinyl pyridine), both bearing 4-vinyl pyridinium units as the cationic
groups.44 Compared with their random analogs, the block copolymers
allow for better accumulation of the cationic groups. As a result,
the block polymers display better antibacterial activity against
Pseudomonas aeruginosa and S. aureus than the random polymers.
In this system, they suggested that the higher 4-vinyl pyridine unit
concentration on the surface of the block copolymers lead to the better
antibacterial activity. Kuroda and co-workers also examined the
antibacterial and hemolytic activities between amphiphilic block and
random copolymers of poly(vinyl ether) (Figure 3).45 Interestingly,
their bactericidal activities against E. coli are similar in this work,
but the block copolymers display a superior biocompatibility to
Dendritic and hyperbranched cationic polymers. Dendrimers are
welldefined macromolecules with narrow polydispersity and definite
chemical structures. The high charge density on surfaces is one of
the most advantageous characteristics for dendrimers as effective
microcidal agents. Cooper and co-workers investigated the
structure?activity relationships of poly(propylene imine) dendrimers as
polymeric antimicrobials.46 It is noteworthy that the generation of
dendrimers, spacer length of the hydrophobic groups and type of
counteranions are of great importance in the inhibitory process. Their
influences are suggested to be complicated when several factors are
considered simultaneously. For example, higher generation of
dendrimers means greater amount of ammonium groups, enabling
stronger attachment to microbial membranes. But in the meantime,
the permeability of these biocides through microbial membranes
would be weakened to some extent due to the larger polymeric size.
The overall advantages of dendrimers to general polymeric disinfectant
include strong adsorption and binding to the microbial membranes
and high capability to disrupt the normal physiological activities
Compared with dendrimers, the hyperbranched polymers are
relatively easier to be synthesized in one pot. Mata and co-workers
compared hyperbranched polymers and dendrimers? biocidal
potency.47 Interestingly, the ammonium-terminated hyperbranched
polymers showed similar antibacterial effect to the analogous
dendrimers. It should be noted that it may not be appropriate to study the
structure?activity relationship by hyperbranched polymers, because
their topological structures cannot be controlled in a precise way. But
for practical concerns, the one-pot preparation of hyperbranched
polymers may benefit to mass production. The MICs of this kind of
antimicrobial cationic polymers were in range of 4?16 ?g ml ? 1,
which indicate considerable antimicrobial activity against E. coli and
S. aureus. Therefore, their applications as a kind of promising
antimicrobial materials are highly anticipated.
SECONDARY STRUCTURAL DESIGNS OF ANTIMICROBIAL
In addition to the primary structures of antimicrobial cationic
polymers, their secondary structures can influence the interactions
with microbial membranes as well, thus regulating their antimicrobial
activity. The secondary structures of antimicrobial cationic polymers
can be mainly formed through two ways: one is ?-helical
conformation; and the other is microbe-induced globally amphiphilic
conformation.48 By controlling the secondary structures, the
hydrophobic groups and the cationic groups can be rationally allocated and
directly enriched toward improving the antimicrobial activity.49
It should be pointed that primary and secondary structural designs
are roughly classified for the simplicity of discussion. In fact, primary
structure is the basis of secondary structure, suggesting that the
influence of primary structure and secondary structure on
antimicrobial property cannot be fully separated.
Plenty of antimicrobial peptides (AMPs) with considerable
antimicrobial activity have been discovered in nature.50?54 Most of them also
contain two kinds of amino-acid residues: the hydrophilic and the
hydrophobic ones.55 It was revealed that the ?-helical conformation of
AMPs can benefit to their antimicrobial performances. Owing to the
?-helical conformation, the hydrophilic and the hydrophobic groups
of AMPs are allocated to the opposite sides of the helix and divided
into two different regions, a hydrophilic region and a hydrophobic
region. In the presence of pathogenic microbes, the hydrophilic region
of AMPs with highly enriched positive charges is strongly adsorbed
onto the surface of microbial membranes. And then, the hydrophobic
region tends to insert into the membranes and disrupt them, thus
leading to the death of microbes.56,57 Although significant
advancements of AMPs have been achieved, they are normally too expensive
to be widely used in practical applications.
Inspired by ?-helical conformation of AMPs, many research works
have focused on improving the ?-helical ?-peptides and peptoids for
antimicrobials.58?61 As shown in Figure 4, Gellman and co-workers
reported an artificial ?-helical ?-peptides displaying antimicrobial
activity against E. coli, Bacillus subtilis, Enterococcus faecium and S.
aureus, which is similar to the natural peptide (magainin).62 The MICs
to these four kinds of bacteria were 6.3, 1.6, 12.5 and 3.2 ?g ml ? 1,
respectively, by incubating the bacteria for 6 h at 37 ?C. One of the
advantages of the above ?-helical ?-peptides is that it exhibits almost
non-hemolytic effect compared with magainin. Antimicrobial
behaviors of ?-helical ?-peptides have been well explored, though it is not
easy to achieve their mass production for further applications.
Induced globally amphiphilic conformation
Along with the further exploration of AMPs, it is found that some of
them without ?-helical conformation can still exhibit the
antimicrobial activity. Another kind of the secondary structure of
AMPs should be responsible for their antimicrobial performances,
which is named as the biomembrane-induced globally amphiphilic
conformation. At first, DeGrado and co-workers successfully
fabricated a kind of globally amphiphilic poly(methacrylate) derivatives as
antimicrobials by randomly copolymerizing hydrophilic monomers
and hydrophobic monomers.63 After that, as proposed by Stahl and
co-workers, the antimicrobial cationic polymers contained cationic
and lipophilic subunits and adopted irregular conformations, which
could be induced by biomembrane surface into globally amphiphilic
conformations. The globally amphiphilic conformation could perform
the key roles for considerable antimicrobial activity, as shown in
Figure 5.64 It is found that higher ratio of cationic groups can benefit
to reduce the hemolytic effect, while higher ratio of hydrophobic
groups is of great importance for antimicrobials. They utilized
minimum hemolytic concentration to display biocompatibility of
antimicrobial cationic polymers. By balancing the ratio of cationic
groups and hydrophobic groups in the random copolymers, they can
achieve relatively low hemolysis and high antimicrobial activity with
the aid of the globally amphiphilic conformation. The bacteria were
incubated at 37 ?C for 6 h for MIC measurements. It is found that the
minimum hemolytic concentration/MIC ratio is 32 against pathogenic
bacteria (E. coli, B. subtilis, S. aureus and E. faecium).
For further decreasing the hemolysis of globally amphiphilic
antimicrobial cationic polymers, Kuroda and co-workers investigated
block and random amphiphilic copolymers as mentioned before.45
They found that block and random amphiphilic copolymers with
similar monomer compositions represent the same level of
antibacterial activity; however, the block ones exhibit lower hemolysis compared
with the random ones. Because the hydrophobic interaction is more
important for hemolysis of RBCs than the electrostatic interaction, and
block amphiphilic copolymers can self-assemble into single-molecule
cationic nanoparticles with a hydrophobic core, making their
hydrophobic groups difficult to insert into the cell membranes of RBCs.
This can reduce the hemolytic effect of block amphiphilic copolymers
to RBCs. On the contrary, the hydrophobic groups of the random
amphiphilic copolymers cannot be protected in this way, thus leading
to their higher hemolysis. Therefore, the regular conformation of
globally amphiphilic antimicrobial cationic polymers is beneficial for
improving their biocompatibility, which needs to be considered in
their secondary structural design.
Till now, many kinds of polymeric backbones of globally
amphiphilic antimicrobial cationic polymers have been developed.65?68 By
varying the specific structures of cationic groups and hydrophobic
groups, the antimicrobial activity against particular microbes can be
selectively enhanced as well.69?77 It should be noted that the physical
chemistry behind the globally amphiphilic antimicrobial cationic
polymers needs to be studied furthermore for providing the guidelines
for fabrication of antimicrobial materials with tailor-made structures
HOST?GUEST SYSTEMS FOR ANTIMICROBIALS
A host?guest system refers to a host?guest complex involving a guest
molecule that can be incorporated into the cavity of a macrocyclic
host.78 The host?guest complexation is driven by noncovalent
interactions. In contrast with covalent bonds, the dynamic nature of
noncovalent interactions can impart the host?guest systems with the
abilities to be reversible, degradable and adaptive. By combining the
host?guest systems with antimicrobial cationic polymers, these
advantages can be inherited into new antimicrobial materials with switchable
Regulation of antimicrobial activity
As mentioned before, the cationic groups and hydrophobic groups of
antimicrobial cationic polymers are two key motifs for antimicrobials.
From another perspective, they can be also regarded as the guest motifs
for host?guest complexations. By using a water-soluble macrocyclic
host, such as cucurbit[n]urils (CB[n]s)79 and cyclodextrin,80 the
hydrophobic group can be encapsulated into the cavity of the host.
Besides, the cationic group can further enhance the host?guest
complexation by introducing electrostatic interactions. In this way,
the antimicrobial activity of antimicrobial cationic polymers is able to be
regulated. There are three possibilities for this regulation: antimicrobial
switch; antimicrobial enhancement; and antimicrobial reduction.
As for the antimicrobial switch, Wang and co-workers reported the
first example of a host?guest system based on cationic poly(phenylene
vinylene) derivative (PPV) and CB[
] for switching the antimicrobial
activity reversibly (Figure 6).81 PPV with quaternary ammonium side
chains alone represented good antibacterial activity against E. coli. The
cationic PPV could close to the surface of bacteria by electrostatic
interaction, and hydrophobic side chains caused the membranolysis.
When the PPV is complexed with CB[
], the hydrophobic groups lose
the capability for inserting into the membrane of bacteria. The
antibacterial activity of PPV can be recovered by removing CB[
through the competitive replacement. In addition, a similar idea can
be extended to poly(fluorene-co-phenylene) derivative (PFP) for
switching on and switching off its antibacterial activity.82
For continuously controlling the antimicrobial activity, our group
developed a general strategy for fabrication of polypseudorotaxane
with tunable antibacterial activity,83 as shown in Figure 7. As a proof
of the concept, ?-poly-L-lysine was chosen as the model polymer,84
] was selected as the macrocyclic host. ?-poly-L-lysine is a
natural polymer approved as a nutritional food preservative. On the
CH3 or H
CH2 C O (CH2CH2 O)6 C C CH2
basis of host?guest complexation, it can be easily incorporated into CB
] to form a polypseudorotaxane. By simply tuning the molar ratio of
] to ?-poly-L-lysine, the antibacterial activity of this
polypseudorotaxane against E. coli can be fine-regulated in a wide range of the
inhibition ratio from 0 to 100%.
Host?guest strategy can also help to improve the performance of
antimicrobial cationic polymers. For example, Wang and co-workers
] to crosslink the phenylalanyl-poly(ethylenimine)
(PhePEI) to obtain a hyperbranched antimicrobial cationic
polymer.85 Compared with PhePEI itself, crosslinked PhePEI/CB[
hyperbranched polymers exhibit higher antibacterial activity. Thus,
] is regarded as the supramolecular activator for antibacterial
regulation. By manipulating the molar ratio of PhePEI to CB[
antibacterial activity could also be easily regulated as well.
Selective differentiation for microbes
Differentiation of various microbes has an important role in clinical
antimicrobial treatments, because some of the microbes are
pathogenic and some of them are harmless or even beneficial for human
body. It should be noted that killing all the microbes without
differentiation may destroy the perfect balance among different
microbes in human body. For this concern, the host?guest systems
of antimicrobial cationic polymers can also help to this point. For
example, Wang and co-workers reported that with the help of CB[
the above mentioned system of PFP-CB[
] can display different
responses in interaction with various microbes, as shown in
Figure 8.86 Wang and co-workers first used the PFP-CB[
on the surface of bacteria, then amantadine (AD) was utilized to
release the encapsulated hydrophobic side chains of the PFP. During
this in situ disassembly process, the change ratio of fluorescence
intensity to different microbial samples represented quite different.
The optical signal changes to both Gram-negative bacteria (P.
aeruginosa and E. coli) and fungi (Saccharomyces cerevisiae and Candida
albicans) decrease greatly, while the change of fluorescence intensity to
Gram-positive bacteria (B. subtilis, S. aureus and E. faecalis) increases
after adding AD. Thus, it can be used as a supramolecular fluorescent
probe to selectively discriminate different kinds of microbes with fast
responsiveness. The reason behind this phenomenon can be ascribed
that the cell membrane of Gram-negative bacteria, peptidoglycan of
Gram-positive bacteria and mannatide of fungi endow them with
unique interfacial properties, thus resulting in different interaction
ability with PFP-CB[
] before and after disassembly by AD. Previous
reports had demonstrated that the interactions to Gram-negative
bacteria and fungi are mainly driven by electrostatic interactions, and
Gram-positive bacteria could be driven by hydrophobic interactions.
Thus, the disassembled PFP-CB[
] by adding AD displays better
inserting abilities to Gram-positive bacteria. This phenomenon
indicates that the various surface properties of different microbes
could lead to different interactions between pathogens and
antimicrobial cationic polymers. Similar strategy could be extended to many
other kinds of antimicrobial cationic polymers and water-soluble
Compared with small-molecule bactericides, antimicrobial cationic
polymers can be easily processed for fabricating antimicrobial
surfaces.87?89 Such antimicrobial surfaces have great potentials for
combating infections in the areas such as medical devices, clinical
treatments and so forth.90?92 For successful fabrication of
antimicrobial surfaces, there are two convenient methods for introducing
antimicrobial cationic polymers: one is the covalent modification
and the other is the noncovalent self-assembly. In recent years, lots of
research works have employed reversible chemistry into the surfaces in
molecular level or modified their mesoscopic structures for improving
their antimicrobial performances.
Utilization of reversible chemistry in antimicrobial surfaces
Previously, dead microbes, staying on the antimicrobial surfaces,
render them losing their antimicrobial activity, thus making them fail
to recycle. To address this problem, the reversible chemistry is
introduced in antimicrobial surfaces. The key to tackle this problem
is to transform the antimicrobial surfaces into the antifouling ones,
thus leading to free leaving of dead microbes. Then, the antimicrobial
activity can be recovered by transforming the antifouling surfaces into
the antimicrobial ones once again. For example, Jiang and co-workers
designed an antimicrobial surface based on cyclic lactones, as shown in
Figure 9.93 At first, this surface is high positively charged, which
attracts and kills microbes. After that, the hydrolysis of cyclic lactones
on the surface can transform it into a zwitterionic one with typical
antifouling property, thus releasing dead microbes from the surfaces.
Then, the cyclic lactones can be regenerated by reversible
bondforming reactions on the surfaces, thus recovering their antimicrobial
In addition to reversible covalent bonds, the host?guest interaction
can be also used in this case. For example, Chen and co-workers
developed a supramolecular versatile strategy for reversible control
over the antimicrobial surface.80 In detail, an adamantine-containing
polymer is attached to the surface initially, and then the
?-cyclodextrins modified with quaternary ammonium salts (CD-QAS) bind with
the adamantine groups on the surface by host?guest interactions, thus
endowing it with antimicrobial activity. As a result, bacteria can be
attracted and killed on this surface. For cycle uses, the surface is
treated with SDS and dead bacteria can be eliminated from the surface
along with CD-QAS, thus regenerating this surface.
Construction of the mesoscopic structures in antimicrobial surfaces
Efforts in antimicrobial surfaces have not only focused on controlling
their structures in molecular level but also devoted to constructing
their mesoscopic structures for improving their antimicrobial
performances. For instance, Chan-Park and co-workers devised an
antimicrobial surface based porous polymeric hydrogels, as shown in
Figure 10.94 It is found that the porous structures of the hydrogels
with abundant positive charges can adsorb anionic phospholipids
from microbial membranes and disrupt them, thus killing microbes.
This surface is regarded as an ?anion sponge? that exhibits broad
antimicrobial activity against E. coli, Fusarium solani, S. aureus and
P. aeruginosa. Similar strategies may be extended to many kinds of
porous hydrogels or other porous materials. It is believed that such
?anion sponge? design may open up a new avenue for fabricating
In conclusion, we have summarized the designs of antimicrobial
cationic polymers from primary to secondary structures, from
covalent to noncovalent synthesis, and from bulk to surface. In
general, the cationic and hydrophobic groups of these polymers
should be rationally devised and regularly allocated for optimizing
their antimicrobial performances and biocompatibility.
Although many systems of antimicrobial cationic polymers have
been developed, there still remain some important issues that need to
be studied. First, the antimicrobial mechanism should be investigated
furthermore and many new potential mechanisms need to be
explored. Second, the gap between the antimicrobial performances
of these polymers in aqueous solution and on the different kinds of
surfaces is necessary to be bridged. Third, these polymers with low
microbial drug resistance may be useful for clinical treatments of
microbial infections. Finally, the precision synthesis of antimicrobial
cationic polymers is required for establishing the fundamentals of
structure?activity relationships, while simple and economic mass
production is highly desirable for practical applications.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
The research was supported by National Natural Science Foundation of China
(21434004). We thank to Dr Jiang-Fei Xu and Dr Haotian Bai for helpful
Yuchong Yang received his Bachelor?s degree in Chemistry from Sichuan University in 2015. He joined Professor Xi Zhang?s group as a
PhD student in Department of Chemistry at Tsinghua University since August 2015. Now, his research interests are focused on the
supramolecular antimicrobial materials, supramolecular free radicals and functional supramolecular polymers.
Zhengguo Cai received his Bachelor?s degree in Chemistry from Tsinghua University in 2016. During August 2016 to July 2017, he
joined Professor Xi Zhang?s group at Tsinghua University as a research assistant, where he focused on supramolecular polymers and
supra-amphiphiles. From August 2017, he started pursuing PhD degree of Chemistry at Duke University, Durham in USA. His research
interests are interdisciplinary area of chemistry, biology and material science, including stimuli-responsive polymers, targeted delivery
systems, supramolecular polymers and molecular sensors.
Zehuan Huang received his Bachelor?s degree from Department of Chemistry, Tsinghua University in 2013. After that, he started his
PhD research under the supervision of Professor Xi Zhang in the same department. His research interests are mainly focused on the
controllable supramolecular polymerization, functional polypseudorotaxanes, host?guest chemistry of cucurbiturils and supramolecular
Xiaoyan Tang started pursuing her PhD degree of Chemistry in Department of Chemistry, Tsinghua University, under supervision of
Professor Xi Zhang since August 2015. She received her Bachelor?s degree in Chemistry from Jilin University in 2015. Her research
interests are focused on supramolecular catalysis and supramolecular polymerization.
Xi Zhang is a professor from the Department of Chemistry of Tsinghua University, Beijing, China. He received BSc in Analytical
Chemistry, MSc and PhD degrees in Polymer Chemistry and Physics at Jilin University under the supervision of Professor Jiacong Shen
and Professor Helmut Ringsdorf (Johannes Gutenberg-Universit?t Mainz). He joined the Department of Chemistry at Jilin University as
a lecturer in 1992 and was then promoted to be a professor in 1994. He moved to Tsinghua University in late 2003. Currently, he serves
Director of the Department of Chemical Science, National Natural Science of Foundation of China (NSFC); Director of Academic
Committee of Tsinghua University; and Vice President of Chinese Chemical Society. He was selected as a Member of Chinese Academy
of Sciences (2007), RSC Fellow (2008) and ACS Fellow (2016). His main scientific interests are in the areas at the cutting edge of
supramolecular chemistry and polymer chemistry, including supra-amphiphiles, supramolecular polymers, Se-containing polymers,
organized molecular films and single-molecule force spectroscopy.
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