Boronic Acid Functionalized Photosensitizers: A Strategy To Target the Surface of Bacteria and Implement Active Agents in Polymer Coatings

Article abstract of DOI:10.1002/anie.201703398

Advanced methods for preventing and controlling hospital-acquired infections via eradication of free-floating bacteria and bacterial biofilms are of great interest. In this regard, the attractiveness of unconventional treatment modalities such as antimicr

Full text of DOI:10.1002/anie.201703398

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Accepted Article
Title: Boronic Acid-Functionalized Photosensitizers: a Straightforward
Strategy to Target the Sweet Site of Bacteria and Implement
Active Agents in Polymer Coating
Authors: Anzhela Galstyan, Roswitha Schiller, and Ulrich Dobrindt
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703398
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Boronic Acid-Functionalized Photosensitizers: a Straightforward
Strategy to Target the Sweet Site of Bacteria and Implement Active
Agents in Polymer Coating
Anzhela Galstyan,* Roswitha Schiller and Ulrich Dobrindt
Abstract: Advanced methods for preventing and controlling hospital-
acquired infections via eradication of free-floating bacteria and
bacterial biofilms are of great interest. In this regard, the
attractiveness of unconventional treatment modalities such as
antimicrobial photodynamic therapy (aPDT) continues to grow. This
study investigated a new and innovative strategy for targeting
polysaccharides found on the bacterial cell envelope and the biofilm
matrix using the boronic acid functionalized and highly effective
photosensitizer (PS) silicon(IV) phthalocyanine. This strategy has
been found to be successful in treating planktonic cultures and
biofilms of Gram-negative E. coli. An additional advantage of boronic
acid functionality is a possibility to anchor the tailor made PS to
poly(vinyl alcohol) and to fabricate a self-disinfecting coating.
are known to induce degradation of carbohydrates and are used
to treat biofilm-related infections.[6] In this regard, PSs capable of
binding to the main components of the biofilm matrix such as
polysaccharides can disrupt its architecture upon irradiation and
generate access to bacteria, providing an important step forward
in photodynamic biofilm inactivation. Once the biofilm is
dispersed, the bacterial cell can be killed by antibiotics,
bacteriophages, macrophages or by the photodynamic action of
the PS itself. Extracellular polysaccharides known as bacterial
glycocalyx are also considered as one of the major structural
components of the bacterial cell surface (up to 75% of surface)
and contribute to the structural integrity of the bacterial cell.[7]
This important cell membrane constituent is of crucial
importance for the survival of Gram-negative bacteria: mutants
unable to synthesize or export such polysaccharides are known
to be highly sensitive to the killing by antibiotics and the host
Antibiotic resistance has become an urgent demand in the field
of health care[1] and current challenges include not only the
increasing spread of drug-resistant strains but also the ability of
bacteria to form biofilms on a variety of living and non-living
surfaces, inducing a new type of resistance.[2] Antibiotics
targeting biosynthetic processes in growing cells become
useless for the treatment of slow-growing or non-growing
bacteria in biofilms. This leads to a search for more effective
therapeutic modalities. Antimicrobial photodynamic therapy
(aPDT) is an alternative and very effective method for treatment
of bacterial infections.[3] It takes advantage of the interaction
between light and a photosensitizing agent (PS) to initiate the
formation of reactive oxygen species (ROS) responsible for the
bacterial inactivation. However, even very effective PSs require
high PS concentrations and light doses to treat biofilms.[4] The
main reason behind this is the formation of multicellular bacterial
communities held together via self-produced extracellular
polymeric substances (EPS). They play a protective role and
prevent penetration and subsequent action of the drugs. The
biofilm matrix is a complex milieu where polysaccharides
together with other major classes of macromolecules like
proteins, nucleic acids, and lipids constitute the elastic part of
the biofilm and provide mechanical stability to it.[5] Enzymes,
such as the glycoside hydrolase dispersin B or alginate lyase
immune
system.[8]
Moreover,
high
amounts
of
lipopolysaccharides (LPS) released from bacteria can trigger an
immune response, leading to endotoxic shock and in extreme
cases to death. Recently, several studies have examined the
efficacy of photoactive conjugates targeting LPS components.
Liu et al. have employed LPS neutralizing peptide–porphyrin
conjugates for effective photoinactivation and intracellular
imaging of Gram-negative bacterial strains.[9] Wong and
coworkers demonstrated that a heteromultivalent dendrimer
nanoplatform binding to LPS serves as an effective method for
bacterial detection or bacteria-targeted drug delivery.[10] Due to
the low affinity to substrates, saccharide recognition is usually
very challenging. Yet, this could be effectively achieved using
the ability of boronic acids to form cyclic boronate five- or six-
membered esters with cis-1,2- or 1,3-diols of carbohydrates
]
through the formation of a pair of covalent bonds.[11 Lack of
apparent toxicity and in vivo stability issues make boronic acid
functionalized compounds very attractive for medical
applications.[12] Due to their unique properties coupled with their
stability and ease of handling boronic acids are also suitable
building blocks for construction of advanced functional materials
that can be used as coatings for invasive medical devices.[13]
Herein we report an effective and straightforward approach to
target planktonic Gram-negative bacteria and the bacterial
biofilm matrix using boronic acid functionalized PS. Photo-
triggered cytotoxicity of obtained PS could be further extended
via incorporation of it into poly(vinyl alcohol) (PVA) coatings to
create a material with photo-bactericidal activity (Figure 1).
The use of silicon(IV)phthalocyanine (SiPc) as a photosensitizer
is very attractive due to its long-wavelength absorption, high
singlet oxygen generation and suitable toxicology and
biocompatibility profiles.[14] The diversity of modification sites of
SiPcs enables the design of PSs with additional characteristics,
such as water solubility, favorable photophysical properties, and
target specificity.[15]
[*]
Dr. A. Galstyan
Center for Nanotechnology, Physikalisches Institut
Westfälische Wilhelms-Universität Münster
Heisenbergstrasse 11, 48149 Münster (Germany)
E.mail: anzhela.galstyan@wwu.de
Dr. R. Schiller, Prof. Dr. U. Dobrindt
Institut für Hygiene
Westfälische Wilhelms-Universität Münster
Mendelstraße 7, 48149 Münster (Germany)
Supporting information for this article can be found under:
http://dx.doi.
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Figure 1. a) Schematic illustration of the interaction between the photosensitizer and polysaccharides of the bacterial cell membrane and the biofilm matrix; b)
Schematic illustration of the implementation of AGA405 into a poly(vinyl alcohol) matrix and SEM images of swollen and freeze-dried hydrogel coating.
The boronic acid functionalized photosensitizer AGA405 and an
appropriate control phthalocyanine lacking the boronic acid
photobleaching was used to obtain  in aqueous media.(Figure
2 and Table 1). Relevant photophysical data for the Pc1 are
summarized in the Supporting Information.
substituents
Pc1
were
synthesized
starting
from
4-nitrophthalonitrile and 3-hydroxypyridine.[16] Synthesis of
diiminoisoindoline in an intermediate step was conducted to
increase the tendency towards cyclization. SiPc was readily
formed in the presence of SiCl4. Exchange of chlorine atoms
was achieved via hydrolysis with ammonium hydroxide solution.
To this end, boronic acid functionality was introduced via
quaternization of the pyridine units on the peripheral positions of
the macrocycle yielding AGA405. Methylation of pyridine units
using dimethylsulfate yielded Pc1 (for details see section 1.2 in
the Supporting Information). For both PSs, the partition
coefficients obtained were similar (LogPAGA405= -1.07, LogPPc1 = -
0.98).
The electronic absorption and basic photophysical data of
AGA405 and Pc1 were measured in N,N-dimethylformamide
(DMF), water and phosphate buffered saline (PBS) and the data
are summarized in Table 1 and section 2 of the Supporting
Information. AGA405 displays typical absorption spectra of non-
aggregated phthalocyanines, with a B-band around 355 nm, and
an intense and sharp Q-band at 674 nm in DMF and 678 nm in
water, which strictly followed the Beer-Lambert law (Figure S1,
Supporting Information). Upon excitation at 610 nm in DMF
solution AGA405 showed a strong fluorescence emission at 686
nm with a fluorescence quantum yield F = 0.33. The behavior
of AGA405 in water (λmax = 692, F = 0.29) is almost similar to
that of measured in DMF. The fluorescence lifetimes were also
fully comparable in both solvents. Lowered molar absorption
coefficients of AGA405 in PBS point towards the formation of
aggregates, most likely due to the self-condensation of boronic
acid groups. The aggregation-disaggregation equilibrium was
found to be temperature and pH dependent (Supporting
Information, section 2.9) Upon excitation at 610 nm, AGA405
generates singlet oxygen O2(1Δg), evidenced by its near-infrared
photoluminescence at 1270 nm. In DMF the singlet oxygen
quantum yield () was determined relative to the tetra-t-
butylphthalocyaninato zinc(II) using the direct method. The rate
of 9,10-anthracenediyl-bis(methylene)dimalonic acid (ABMDMA)
Figure 2. Absorption, fluorescence and 1O2 emission spectra (λexc = 610 nm)
of AGA405 in N,N-dimethylformamide (solid line) and water (dashed line).
Table 1. Electronic absorption and photophysical data for AGA405.
c
/ nsb
F
 d
λem /nma
AGA 405
λabs/nm (log ε)
356 (4.64)
604 (4.36)
674 (5.08)
686
750
in DMF
4.57
0.33
0.51d
353 (4.45)
611 (4.12)
678 (4.92)
692
760
in H2O
4.55
0.29
0.18e
b
a Excited at 610 nm. Excited at 635 nm. c Quantum yields were measured in
d
an integrating sphere system. Quantum yield was measured using the
relative method and ZnPc as the reference. e Quantum yield was measured
using photochemical monitor bleaching rates and methylene blue as the
reference.
The chemical composition of the carbohydrates in biofilms and
outer membrane-associated lipopolysaccharides is often unique
to a specific bacterial strain.[17] To investigate the feasibility of
our hypothesis, the binding affinity of AGA405 to different
carbohydrates
were
examined.
Five
representative
carbohydrates D-glucose, D-fructose, D-mannose, D-galactose
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and 3-deoxy-D-manno-2-octulopyranosonic acid (KDO) were
used as a substrate model for the compounds of biological
interest that would represent potential targets of PS binding.
Intrinsic fluorescence of AGA405 in PBS buffer was changed to
polysaccharide layers on the outer membrane of these strains,
which increases the cell surface’s impassibility. All E. coli strains
exhibit low sensitivity to photosensitization by Pc1 due to the
weak binding of the PS to bacterial outer membrane. Analog of
Pc1 differing only in the nature of the counter ions was
previously reported by Mantareva et al. also found to exhibit
reduced binding to bacterial cells.[21] Their studies on Gram-
positive (S. mutants, E. faecalis) and Gram-negative (A.
actinomycetemcomitans, P. intermedia) bacteria showed a very
low photodynamic response.[21]
The E. coli biofilms used in this study were developed during
48 h and treated with a 10°µM solution of AGA405 for an
incubation period of 30 min. In combination with the light fluency
of 18 J/cm2, AGA405 significantly decreased biofilm metabolism
(measured by the application of the XTT reduction assay, Figure
4a) as well as biofilm biomass (measured by crystal violet
staining, Figure 4b). The observed biofilm mass of the E. coli
strains 536, 3025/11 and 3588/11 was reduced by approx. 50%
in comparison to the untreated control. The reduction of biofilm
mass was accompanied by an almost complete loss of
metabolic activity of the bacteria. Although a PDT-induced
reduction of the cellular metabolism occurred for E. coli strain
04441/201/06 as well, the reduction of the biomass was less
profound in this case. This could be attributed to the tendency of
this strain to form more robust biofilm.
a
different extent depending on the added saccharides,
indicating the proposed boronic acid-diol binding interaction
(Figure S8, Supporting Information).
As a consequence of the different membrane composition the
light activated mode of microbial killing is significantly higher for
Gram-positive rather than Gram-negative organisms.[18] In
addition, the increasing incidence of antibiotic-resistant
infections by Gram-negative bacteria [19] calls for renewed efforts
to develop more effective PSs for combating Gram-negative
pathogens. Although the bacterial membrane is likely to be the
main target of PS, studies regarding the dependency of PS
phototoxicity on the outer membrane composition of closely
related bacteria are scarce. To address this issue, four
extraintestinal pathogenic E. coli strains with distinct surface
polysaccharide structures 536, 04441/201/06, 3025/11 and
3588/11 were used to assess the photoinactivation efficiency of
AGA405 and Pc1. The introduction of positive charges not only
provides solubility to the otherwise highly insoluble
phthalocyanine macrocycle, but also provokes electrostatic
interaction with the negatively charged outer membrane of E.
coli. Together with the multipoint binding of AGA405 to LPS-
constituents through boronic acid-diol interactions, an incubation
time of less than 15 min is sufficient in order to achieve
significant binding of PS to microbial cells, even after three
washing steps. In contrast, binding of Pc1 under these
conditions was substantially low, emphasizing the importance of
the PS-membrane interaction.[20]
Figure 3. Histograms showing the photodynamic inactivation of E. coli in
planktonic cultures treated with a) AGA405 and b) Pc1 ([PS]=10 µM). The
number of colony forming units (CFU) indicates the presence of live bacteria in
the aliquots that were plated. Results are presented as mean ± SD.
The bacterial cellular uptake efficiency was cell-line dependent
and uptake levels showed to be influenced by the composition of
the bacterial glycan coat (Figure S11, Supporting Information).
Nevertheless, AGA405 can efficiently label all E. coli strains
tested, as seen in the fluorescence microscopy images (Figure
S12, Supporting Information).
Illumination of E. coli cells which had been exposed to 10 µM
AGA405 caused a considerable decrease in cell survival
exhibiting strain-dependent photocytotoxicity (Figure 3a). E. coli
strains 536 and 04441/201/06 photosensitized under identical
conditions showed similar decreases in CFU/ml. For E. coli
strains 3025/11 and 3588/11 the photo bactericidal effect was
lower. This could be explained by the presence of thick
Figure 4. Histograms showing the a) viability and b) biomass reduction of 48 h
biofilm of E. coli cells upon photodynamic treatment ([PS] = 10 µM, control-
black, light dose
c) Representative scanning electron microscopy (SEM) images of treated and
untreated biofilm samples.
= ± SD.
18 J/cm2). Results are presented as mean
The morphology of bacterial cells and extracellular surfaces of
biofilms were visualized by scanning electron microscopy. Upon
irradiation in the presence of 10°µM AGA405 marked changes
in the EPS architecture and the bacterial cell membrane was
observed (Figure 4c). Biofilms were mostly disrupted and non-
aggregated single bacterial cells were detected. The surface
structures of bacterial cells also showed obvious changes upon
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irradiation: they became wrinkled and some cells lost their
cellular integrity. The photodynamic action of Pc1 on biofilms
was significantly lower as compared with AGA405 (Figure S15
and Figure S16, Supporting Information). Even though further
detailed studies are required to determine the target specificity,
the dependence of the uptake of PS, and the photo bactericidal
activity in planktonic cultures and biofilms from bacterial glycan
coat suggests an important role of the nature of polysaccharides
in aPDT.
One of the favorable attributes for a PS to be used in aPDT is
the possibility to implement it in formulations for delivery or for
antibacterial coatings.[22] So far two main strategies were used
for immobilization of PSs to a substrate: covalent coupling[23] and
physical adsorption.[24] The use of reversible bonds such as
and Dagmar Zeuschner (MPI, Münster) are gratefully
acknowledged for SEM sample preparation and Martin Bühner
(nanoAnalytics GmbH, Münster) for the SEM measurements.
Johannes Putze is acknowledged for support with cell culture
experiments and Olena Mantel for excellent technical assistance.
AG thanks Cristian Strassert for support.
Conflict of interest
AG has received travelling grant from GlaxoSmithKline.
Keywords: antibiotic resistance • E. coli • bacterial biofilm •
silicon(IV)phthalocyanine • antibacterial coating
boronate esters can enable the design of new systems with
25]
favorable characteristics.[13,
Boronic acids are known to be
very efficient cross-linkers of poly(vinyl alcohol)(PVA),[26] which
is a water soluble polymer with excellent film-forming and
adhesive properties. The use of PVA-based materials in the
biomedical field is steadily increasing, also due to the wide
availability and low cost of this polymer. We used AGA405 to
promote the cross-linking of PVA via formation of reversible
covalent bonds with the hydroxyl groups present in PVA
repeating units. Indeed, SEM images of obtained the PVA-
AGA405 composite produced by the drop-casting method
showed the formation of a uniform network pattern (Figure 1b).
Light-activated antimicrobial properties of the coverslips coated
with the optimized formulation of PVA-AGA405 were explored
using E. coli strain 536. The extent of the cell inactivation
correlated well with the concentration of the released PS (Figure
S18, Supporting Information). This is consistent with the reports
suggesting that the short life and minimal diffusion of the
generated ROS restrict the oxidative damage to the PS in close
proximity to bacteria. Most likely the highly hydrophilic surface of
the PVA-AGA405 coating resulting from the uptake of water into
the polymeric backbone prevents bacterial adhesion to the
surface.[27] This is a very important and desirable feature of
antibacterial coatings that prevents biofilm formation.[28]
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In conclusion, we suggest an effective strategy to modify PSs in
a way that they are able to bind to polysaccharides of the
bacterial cell membrane and biofilm matrix via boronic acid-diol
interaction and destroy it using near-infrared light-mediated PDT.
Moreover the same functionality could be used to implement PS
into PVA based coating. The current results provide new insights
into the formation of dynamic coatings that may have a big
impact in reducing the risk of device-associated infections or can
be used to seal surgical wounds and simultaneously prevent
wound infection. The PVA-AGA405 composite represents a
versatile platform for the development of new materials with a
wide range of application in modern medicine.
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[18] F. F. Sperandio, Y.-Y. Huang, M. R. Hamblin, Recent Pat Antiinfect
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The work of AG was supported by the Deutsche
Forschungsgemeinschaft (DFG), project GA 2362/1-1 and EXC
1003 Cells in Motion – Cluster of Excellence. The work of UD
was supported by the DFG (SFB 1009, TP B05). Karina Mildner
[19] J. M. A. Blair, M. A. Webber, A. J. Baylay, D. O. Ogbolu, L. J. V.
Piddock, Nature Rev. Microbiol. 2015, 13, 42–51.
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Entry for the Table of Contents
COMMUNICATION
Making and Breaking Barriers:
Dr. A. Galstyan, Dr. R. Schiller, Prof. Dr.
U. Dobrindt
Boronic acid-diol interaction was used
to anchor a photosensitizer into the
bacterial cell surface and biofilm
matrix and break the barrier via
photodynamic action. Moreover, the
same functional group enables
implementation of the active agent in
a poly(vinylalkohol) coating providing
a photo-bactericidal barrier against
microbial adhesion.
Page No. – Page No.
Boronic Acid-Functionalized
Photosensitizers: a Straightforward
Strategy to Target the Sweet Site of
Bacteria and Implement Active
Agents in Polymer Coating
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