Membrane-Anchoring Photosensitizer with Aggregation-Induced Emission Characteristics for Combating Multidrug-Resistant Bacteria

Article abstract of DOI:10.1002/anie.201907343

Traditional photosensitizers (PSs) show reduced singlet oxygen (¹O₂) production and quenched fluorescence upon aggregation in aqueous media, which greatly affect their efficiency in photodynamic therapy (PDT). Meanwhile, non-targetin

Full text of DOI:10.1002/anie.201907343

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Accepted Article
Title: Membrane-Anchoring Photosensitizer with Aggregation-Induced
Emission Characteristics for Combating Multidrug-Resistant
Bacteria
Authors: Huan Chen, Shengliang Li, Min Wu, Kenry Kenry, Zhongming
Huang, Chun-Sing Lee, and Bin Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907343
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10.1002/anie.201907343
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COMMUNICATION
Membrane-Anchoring Photosensitizer with Aggregation-Induced
Emission Characteristics for Combating Multidrug-Resistant
Bacteria
Huan Chena, Shengliang Lib*, Min Wua, Kenrya, Zhongming Huangb, Chun-Sing Leeb*, and Bin Liua*
Abstract: Traditional photosensitizers (PSs) show reduced singlet
oxygen (1O2) production and quenched fluorescence upon
aggregation in aqueous media, which greatly affect their efficiency in
photodynamic therapy (PDT). Meanwhile, non-targeting PSs
generally yield low efficiency in antibacterial performance due to their
short lifetimes and small effective working radii. Herein, a water-
dispersible membrane anchor (TBD-anchor) PS with aggregation-
induced emission is designed and synthesized to provide
superefficient 1O2 generation specifically on bacteria membrane.
TBD-anchor possesses energy donor and acceptor subunits to
modulate the bandgap of the PS, and cationic groups were introduced
to target bacterial membrane through electrostatic and hydrophobic
interactions. TBD-anchor showed superefficient antibacterial
performance towards both Gram-negative bacteria (E. coli) and
Gram-positive bacteria (S. aureus). Over 99.8% killing efficiency was
obtained for Methicillin-Resistant Staphylococcus aureus (MRSA)
when they were exposed to 0.8 μM of TBD-anchor at a low white light
dose (25 mW/cm2) for 10 minutes. TBD-anchor thus shows great
promise as an effective antimicrobial agent to combat the menace of
multidrug-resistant bacteria.
negligible drug resistance, low systemic toxicity and minimal side
effects.[2c, 4b, 4c] Conventional PSs, such as TMPyP and Toluidine
blue
O have been used to kill bacteria with moderate
effectiveness.[5] This is because the aggregation of traditional
hydrophobic PSs often causes fluorescence quenching with
reduced singlet oxygen (1O2) generation in aqueous media, which
significantly hampers their bacteria ablation efficacy.[2a] To
address this issue, PSs with aggregation-induced emission (AIE
PS) have been developed to show bright fluorescence and
excellent 1O2 production in the aggregate state, or even as
nanoparticles dispersed in aqueous media.[4d, 4e]
So far, AIE PSs have been successfully used to develop
theranostic probes for cancer.[4j, 4k] Detailed studies reveal that
their killing efficiency can be significantly enhanced when the
probes can selectively target cell organelles, such as cytoplasmic
membrane and mitochondria,[6] as compared to those distributed
in the cell cytoplasm. This is due to the short lifetimes and small
effective radii of the reactive oxygen species.[2c, 7] Motivated by
the initial success, we and others have further developed AIE
probes to detect and kill bacteria.[4i, 4k, 8] These probes generally
share the good feature of light-up response to bacteria, so that
the detection can be done in real time without washing steps.[8a]
Some of these probes also showed obvious dark toxicity, which
combined with light-induced photosensitization to effectively kill
bacteria even under sunlight.[8b] Most of these studies did not
address specificity among different bacteria. Therefore, bacteria
specific theranostic probes have been realized through
bioconjugation between AIE PSs and peptides that are specific to
certain bacteria. One such example is the AIE-Van probe, which
is specific to Gram-positive bacteria.[4i]
The PS sensitivity or its effectiveness in ROS production is
highly dependent on its capability in light absorption and
intersystem crossing (ISC).[4f] ISC can be adjusted through
HOMO-LUMO engineering to realize a small energy gap between
the triplet (T1) and singlet (S1) states. However, as AIE PSs
generally have rotor structures, poor conjugation is often
observed within the molecules, yielding narrow absorption in the
short wavelength region.[4h] In this regard, how to design new PSs
with broad absorption and large molar absorptivity is in high
demand to develop highly effective probes for bacteria detection
and ablation.
Bacterial resistance to conventional antibiotics is one of the
most serious healthcare problems faced by the world today.[1]
Over the past decades, millions of patients have been affected by
various health- and life-threatening bacteria-caused diseases and
the situation has deteriorated with the emergence of multidrug-
resistant (MDR) bacteria.[2] Unfortunately, the number of
infections caused by MDR bacteria has been on the rise.[1b] As
noted in the recent World Economic Forum reports, antibiotic-
resistance poses a serious threat to global health.[3] Therefore,
there is an urgent need for the development of new strategies to
resolve this serious healthcare problem.
Traditional methods such as antibiotic treatment and
radiotherapy have shown limitations in clinical applications,
among which the drug resistance and side effects are the two
2e]
main obstacles.[2c,
Among the emerging antibacterial
therapeutic methods, photodynamic therapy (PDT) has attracted
increasing attention.[4] It utilizes photosensitizers (PSs) to produce
toxic reactive oxygen species for antibacterial treatment, which
has shown great potentials due to the non-invasive nature of PDT,
In this study, we propose an AIE-based membrane-
anchoring photosensitizer (TBD-anchor, as shown in Scheme 1),
which was designed to combine two features, i.e., 1O2 generation
and bacterial membrane anchoring abilities. The molecular
design was started from AP3, since the molecule with D (donor)-
A′ (auxiliary acceptor)-π (π spacer)-A (acceptor) structure could
offer broad absorption in the visible range with effective 1O2
generation.[4b, 4c] Motivated by the fact that cationic groups could
insert effectively into some bacterial membrane,[9] a phenyl ring
with three cationic groups was introduced to AP3, which yielded
TBD-anchor for bacteria imaging and ablation. Detailed studies
[a]
[b]
Huan Chen, Dr. Min Wu, Dr. Kenry, Prof. Bin Liu
Department of Chemical and Biomolecular Engineering, National
University of Singapore, 4 Engineering Drive 4, 117585, Singapore
E-mail: cheliub@nus.edu.sg
Dr. Shengliang Li, Zhongming Huang, Prof. Chun-Sing Lee
Center of Super-Diamond and Advanced Films (COSDAF)
Department of Chemistry, City University of Hong Kong, 83 Tat
Chee Avenue, Kowloon, Hong Kong SAR, P. R. China.
E-mail: lishengliang@iccas.ac.cn; apcslee@cityu.edu.hk
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201907343
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reveal that TBD-anchor has strong 1O2 generation capability with
high efficiency in ablating various bacteria.
Figure 1. a) UV–vis absorption and photoluminescence (PL) spectra of TBD-
anchor. b) PL spectra of TBD-anchor in MeOH/Toluene mixtures with different
toluene fractions (λex = 450 nm). c) The plot of relative emission intensity (III0)
at 650 nm versus the composition of the MeOH/Toluene mixtures of TBD-
anchor. UV–vis absorption spectra of ABDA in the presence of TBD-anchor
(d) and RB (e) under white light irradiation (λ = 400-700 nm). f) Decomposition
rates of ABDA in the presence of TBD-anchor and RB under light irradiation,
where A0 and A are the absorbances of ABDA at 378 nm. [TBD-anchor and
RB] = 5 × 10−6 M, [ABDA] = 5 × 10−5 M. Power of irradiation: 10 mW/cm2.
Scheme 1. Chemical structure and schematic illustration of the mechanisms for
TBD-anchor for bacteria membrane penetration.
To understand the interaction between TBD-anchor and
bacteria, E. coli cells were used for the imaging experiment by
confocal laser scanning microscopy (CLSM) and DAPI (4’,6-
diamidino-2-phenylindole) was used to stain the bacteria DNA. As
shown in Figure 2a-b and Figure S13, DAPI could stain the
bacteria interior with false green color, while the red emission from
the exteria of bacterial was due to the staining with TBD-anchor.
The overlay image (Figure 2c) clearly shows that the outer
bacterial layer is red and the interior is green, suggesting that
TBD-anchor could effectively anchor to the bacterial membrane.
The zeta potential of E. coli was negative (-13.3 mV), which was
increased to positive (15.6 mV) when 5 μM of TBD-anchor was
added to the E. coli mixture (Figure S14). This result suggests
that TBD-anchor could effectively bind to bacteria.[9a, 10]
The synthetic route to TBD-anchor is shown in Figure S1.
The structures of intermediates and TBD-anchor were well
characterized with NMR and mass spectrometer (Figure S2-S9).
TBD-anchor shows a very broad absorption from 300 to 500 nm
with an emission maximum at 650 nm (Figure 1a). As illustrated
in Figure 1b-1c, the anchor shows nearly no emission in pure
methanol solution. With the increase in toluene (a poor solvent of
TBD-anchor) volume content in the methanol/toluene mixtures
from 0 to 60%, slight enhancements in emission intensity were
observed. When the toluene fraction was more than 60%,
significant emission enhancements centered at 650 nm were
noted owing to the aggregate formation of TBD-anchor (Figure
1b). The result indicates that TBD-anchor processes
aggregation-induced emission characteristic.
A standard Isothermal Titration Calorimetry (ITC) assay was
then performed to further investigate the binding mechanism of
TBD-anchor to bacterial membrane. The observed enthalpy
(ΔHobs) varied distinctively with the addition of the anchor (Figure
S15), indicating its effective interaction with E. coli [11]. The
The 1O2 generation capability of TBD-anchor was
investigated by measuring changes in UV-visible spectra of 9,10-
anthracenediyl-bis(methylene)dimalonic acid (ABDA,
a
1O2
indicator) upon white light irradiation (400-700 nm, Figure S10).
Meanwhile, Rose Bengal (RB), a commercial PS, was employed
as a reference. As shown in Figure 1d-f, the absorbance of ABDA
treated with TBD-anchor and RB at 378 nm shows obviously
attenuation with the irradiation time. Importantly, the absorbance
of ABDA in TBD-anchor solution is decreased by 74.7% under
white light irradiation for 5 min, indicating that 7.47 μmol of ABDA
was consumed every min when 5 μM of TBD-anchor was
exposed to the light. As comparison, only 2.92 μmol of ABDA was
consumed for 5 μM of RB under the same condition. Furthermore,
the 1O2 generation quantum yield of TBD-anchor was calculated
to be 0.48 by measuring 1O2 phosphorescence at 1270 nm using
RB as a reference (Figure S11). It is worth noting that TBD-
anchor shows excellent photostability in comparison with other
typical organic dyes (i.e., RB, Ce6 and ICG) when exposed to
white light irradiation because the AIE probe is not easily oxidized
by the photogenerated 1O2 (Figure 1d-1e and Figure S12).
negative ΔHb (-48.6) and ΔSb (-35.5) suggest electrostatic
12]
interactions between TBD-anchor and bacteria.[11b,
The
binding enthalpy varied from negative to around zero after the
anchor addition, indicating hydrophobic interactions.[12b]
Therefore, TBD-anchor could effectively interact with E. coli
through both electrostatic and hydrophobic interactions.
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10.1002/anie.201907343
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E. coli and S. aureus (Figure S18). It is also noted that even 32
μM TBD-anchor has negligible toxicity towards healthy NIH 3T3
cells under both dark and light conditions, which strongly indicates
that TBD-anchor is biocompatible (Figure S19).
Figure 2. Interaction between TBD-anchor and E. coli. CLSM images of E. coli
cells treated with 10 μM TBD-anchor in PBS. a) The bacterial inner parts were
labeled by DAPI with false green color. b) Red emission of the bacterial
membranes stained with TBD-anchor. c) Overlay images of a and b. SEM
Images of E. Coli affiniting with TBD-anchor. d) Blank E. Coli, e) E. Coli treated
with 10 μM TBD-anchor under dark condition, f) E. Coli treated with 10 μM
TBD-anchor under whitle light.
Figure 4. Antibacterial activity of TBD-anchor towards MRSA. a) Inhibition of
MRSA growth by TBD-anchor at 10 μM and Cefoxitin with or without light with
a dose of 15 J/cm2. b) Inhibition of bacteria growth under light irradiation with a
dose of 15 J/cm2 at different PS concentrations. c) Antibacterial activity of TBD-
anchor towards MRSA under different light doses irradiation. d) Images of CFU
for MRSA on agar plate after 5 min treatment with different concentrations of
the TBD-anchor and e) treatment with 1 μM TBD-anchor under different light
doses irradiation.
The morphologies of bacteria with or without TBD-anchor
treatment were obtained by scanning electron microscopy
(Figure 2d-f). The control E. coli (without TBD-anchor treatment
or treated with TBD-anchor in the dark) showed smooth outer
surfaces. However, the outer surfaces of E. coli treated with TBD-
anchor after irradiation were significantly destroyed, thereby
illustrating the bio-impact of the localized generation of 1O2 rooted
from TBD-anchor.[9a]
It is well known that MRSA is one of the most dangerous
drug-resistant bacteria which could induce clinical death
immediately.[1b] We next sought to systematically determine the
antibacterial activity of TBD-anchor. As shown in Figure 4a and
Figure S20,  99.9% of MRSA were killed upon treatment with 10
μM of TBD-anchor under a light dose of 15 J/cm2. As a control,
no significant inhibition was found in the PBS- and Cefoxitin (a
second-generation antibiotic used to treat a wide variety of
bacterial infections)-treated groups, even when the Cefoxitin
concentration was increased to 10 μg/mL ( 23.3 μM). The
excellent antibacterial activity of TBD-anchor in inhibiting the
growth of S. aureus and MRSA cells motivated us to further
investigate the antibacterial activity at low concentrations.
Figures 4b and 4d illustrate that > 98.1% of MRSA were killed at
0.4 μM and the inhibition ability was increased to 99.8% at 0.8 μM
with 15 J/cm2 irradiation, respectively. For the killing ability of S.
aureus (Figure S21-S22), the inhibition percentage is up to >
96.4% at 0.4 μM and 99.3% at 0.8 μM, respectively. This
compares favorably to other commercial PSs. For example, the
concentration of Toluidine blue O used for inhibiting ≥ 99.0% of
MRSA and S. aureus is up to 80 μM under a dose of 30 J/cm2.[5b]
For Ce6, the concentration is up to 40 μM to kill 99.9% of S.
aureus and MRSA with a dose of 15 J/cm2.[4l] The comparison
strongly suggests that TBD-anchor is an excellent antibacterial
PDT agent.
Figure 3. Antibacterial activity of TBD-anchor towards E. coli and S. aureus. a)
CFU (colony forming unit) inhibition of E. coli and S. aureus with a dose of 15
J/cm2. b) Inhibition of TBD-anchor towards E. coli and S. aureus under different
light doses irradiation.
1
As TBD-anchor possessed highly effective O2 generation
ability, it motivated us to investigate their antibacterial PDT ability.
The antibacterial activities of TBD-anchor towards Gram-
negative E. coli and Gram-positive S. aureus were examined by
irradiation under white light (400-700 nm). The standard plate
colony counting method was used to determine the percentage of
live bacteria. The results show that the percentage of live bacteria
decreases significantly with the increasing of TBD-anchor
concentrations upon 15 J/cm2 (irradiation for 10 min at a fluence
of 25 mW/cm2) of white light irradiation. Approximately 96% of E.
coli is inhibited when treated with 5 μM of the TBD-anchor and 2
μM of the anchor can destroy 99.5% of S. aureus (Figure 3a and
Figure S16-S17). The results indicate that TBD-anchor holds
excellent antibacterial activity towards both Gram-positive and
Gram-negative bacteria at low PS concentration upon very low-
Thanks to the excellent antibacterial activity, the antibacterial
PDT performance of TBD-anchor at 5 μM, 2 μM and 1 μM against
the growth of E. coli, S. aureus, and MRSA was further examined
by varying the irradiation dose, respectively. As shown in Figure
3b, Figure 4c, Figure 4e and Figure S23-S24, > 99.9% of all
three bacteria were destroyed at a dose of 15 J/cm2. The inhibition
ability toward S. aureus was 91.1% at an irradiation of 3 J/cm2
and the value was increased to > 99.1% when the dose was 6
dose irradiation, suggesting that TBD-anchor is
a broad
spectrum antibacterial probe. Under the dark condition, negligible
toxicity was observed when 40 μM TBD-anchor was used to treat
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J/cm2. More importantly, 96.8% of MRSA were killed with an
irradiation dose of 3 J/cm2 and the killing ability was increased to
100% at a dose of 6 J/cm2. It is worth noting that the light dose
needed to kill E. coli, S. aureus and MRSA cells with TBD-anchor
was significantly lower than those based on porphyrin, as
described in the literature (30–266 J/cm2)[13] and XF-73 (13.7–
15.2 J/cm2) which is in phase 1 clinical trial as treatment for nasal
decolonization of S. aureus (including MRSA).[14] To the best of
our knowledge, this is the first AIE PS which can effectively ablate
bacteria below micro-molar concentration.[4g, 4j] The antibacterial
performance of TBD-anchor is superior to many reports in the
literature, such as conjugated polyelectrolyte based system[9a]
and other non-AIE PSs.[15] Therefore, TBD-anchor is one of the
most effective antibacterial photosensitizers reported so far
(Table S1).[2c, 4g]
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In summary, we developed an AIE PS (TBD-anchor) with
very efficient 1O2 generation for membrane-targeted antibacterial
treatment, which has achieved multidrug-resistant bacteria
suppression at the nano-molar level. Due to its AIE backbone with
electron-donor and electron-acceptor structural units, TBD-
anchor shows broad absorption in the visible range, while three
cationic groups were introduced into the molecular design for
bacterial membrane anchoring. Fluorescence imaging and ITC
results confirm that TBD-anchor interacts with bacterial cell
membranes through both electrostatic and hydrophobic
interactions. TBD-anchor also shows effective 1O2 generation
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1
with a O2 quantum yield of 0.48. Benefitting from the enhanced
membrane interactions and photosensitizing ability, TBD-anchor
exhibited super-efficient antibacterial capability in destroying S.
aureus and MRSA at low concentration (1-2 μM) and low light
dose (3-6 J/cm2). Interestingly, the anchor also exhibited a strong
capability in killing S. aureus and MRSA at 0.4 μM under white
light of 15 J/cm2. Our study has demonstrated the promising
potential of AIE PS and the anchor strategy for anti-MRSA
treatment.
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We thank the Singapore National Research Foundation (R279-
000-444-281 and R279-000-483-281), the National University of
Singapore (R279-000-482-133) for financial support. This work
was also supported by City University of Hong Kong (CityU
Internal Funds for External Grant Schemes (9678157) and CityU
Applied Research Grant: Project no. 9667160).
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Keywords: antibacterial activity • aggregation-induced emission
• membrane anchor • photodynamic antimicrobial therapy •
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Entry for the Table of Contents
COMMUNICATION
Huan Chen, Shengliang Li*, Min Wu,
Kenry, Zhongming Huang, Prof. Chun-
Sing Lee*, and Prof. Bin Liu*
A
membrane
anchor
(TBD-anchor)
photosensitizer with aggregation-induced
emission provides highly efficient 1O2
generation
specifically
on
bacteria
membrane. Over 99.8% killing efficiency was
obtained for MRSA when they were exposed
to 0.8 μM of TBD-anchor. TBD-anchor thus
shows great promise as an effective
antimicrobial agent to combat the menace of
multidrug-resistant bacteria.
Page No. – Page No.
Membrane-Anchoring Photosensitizer
with Aggregation-Induced Emission
Characteristics for Combating
Multidrug-Resistant Bacteria
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