On-POM Ring-Opening Polymerisation of N-Carboxyanhydrides

Article abstract of DOI:10.1002/anie.202013563

The ring-opening polymerisation of α-amino acid N-carboxyanhydrides (NCAs) offers a simple and scalable route to polypeptides with predicted and narrow molecular weight distributions. Here we show how polyoxometalates (POMs)—redox-active molecular metal-oxide anions—can serve as inorganic scaffold initiators for such NCA polymerisations. This “On-POM polymerisation” strategy serves as an innovative platform to design hybrid materials with additive or synergistic properties stemming from the inorganic and polypeptide component parts. We have used this synthetic approach to synthesise a library of bactericidal poly(lysine)–POM hybrid derivatives that can be used to prevent biofilm formation. This versatile “On-POM polymerisation” method provides a flexible synthetic approach for combining inorganic scaffolds with amino acids, and the potential to tailor and improve the specificity and performance of hybrid antimicrobial materials.

Full text of DOI:10.1002/anie.202013563

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Accepted Article
Title: On-POM ring-opening polymerisation of N-Carboxyanhydrides
Authors: Héctor Soria-Carrera, Isabel Franco-Castillo, Pilar Romero,
Santiago Solans, Jesús M. de la Fuente, Scott G Mitchell, and
Rafael Martín-Rapún
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202013563
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On-POM ring-opening polymerisation of N-Carboxyanhydrides
Héctor Soria-Carrera, Isabel Franco-Castillo, Pilar Romero, Santiago Martín, Jesús M. de la Fuente,
Scott G. Mitchell,* Rafael Martín-Rapún*
Abstract: The ring-opening polymerisation of α-amino acid N-
initiators.[7–9] The surface-initiated ROP of NCAs relies on the
immobilisation of amino groups at the surface that can initiate the
carboxyanhydrides (NCAs) offers a simple and scalable route to
polypeptides with predicted and narrow molecular weight distributions. polymerisation. This attractive concept combines the robustness
Here we show how polyoxometalates (POMs)
–
redox-active
of a metallic support with the high functionality of polypeptides.
Although the controlled binding and assembly of polypeptides
molecular metal-oxide anions – can serve as inorganic scaffold
initiators for such NCA polymerisations. This “On-POM polymerisation” onto inorganic substrates lies at the core of biological-materials
strategy serves as an innovative platform to design hybrid materials
with additive or synergistic properties stemming from the inorganic
and polypeptide component parts. We have used this synthetic
approach to synthesise a library of bactericidal poly(lysine)-POM
hybrid derivatives that can be used to prevent biofilm formation. This
engineering, these scaffolds are not discrete molecules and
mostly comprise noble metals, minerals or metal-oxides such as
hydroxyapatite, calcite, magnetite and silica.
Polyoxometalates (POMs) are molecular metal-oxides with
elevated redox activity that have been employed in fields as
diverse as catalysis, energy and biology.[10–12] These cluster
versatile “On-POM polymerisation” method provides
a flexible
synthetic approach for combining inorganic scaffolds with amino acids, anions can be easily tuned to tailor the physicochemical
and the potential to tailor and improve the specificity and performance
of hybrid antimicrobial materials.
properties for a variety of applications by varying the number
and/or type of metal addenda atom or introducing organic ligands.
Organic hybrids of POMs offer versatile platforms to develop new
materials that potentially combine the properties of both
entities.[13–15] In particular, the well-known Mn-Anderson derivative
can be functionalised with Tris-base producing bis-amino
functionalised POM [MnMo6O18((OCH2)3CNH2)2]3- for post-
reaction development.[16,17] Cronin and co-workers paved the way
Polypeptides are ubiquitous in Nature and perform crucial
roles in signalling, protecting and transport in living organisms.
Most often, synthetic polypeptides are obtained by biosynthesis
or by means of Solid Phase Peptide Synthesis (SPPS), which
reproduce the exact peptide sequence. However, the scalability
of these processes remains challenging.[1] In contrast, the Ring
Opening Polymerisation (ROP) of N-carboxyanhydrides (NCAs)
has emerged as an atom efficient one-pot route to polypeptides
under living polymerisation conditions.[2,3] This approach allows
the scalable synthesis of peptidomimetics that gather the main
towards
hybrid-POM-peptidic
composites
via
covalent
attachment[18] or introducing them in a SPPS-like workflow.[19]
Further, POMs have been also derivatised in such a way that they
act as initiators of radical polymerisations[20,21] or as repeating unit
in a polymer sequence.[22,23]
POMs have been shown to exhibit antimicrobial properties
arising from their redox properties and their interaction with
bacterial cell membranes, which results in membrane puncturing
and cell lysis.[24] Antimicrobial peptides (AMPs) have received
increasing attention because of their rapid action and broad-
spectrum antimicrobial activities. They are usually formed by
sequences combining hydrophobic and cationic amino acids. The
dual functionality arising from these cationic and amphiphilic
properties allows AMPs to attach to the anionic microbial cell
membranes, intercalate into the lipid bilayers and eventually
disrupt the cell membrane.[25] Importantly, libraries of AMPs can
easily be prepared by ROP of NCAs.[26–28]
Since both POMs and polypeptides have each been shown to
exhibit potent antimicrobial properties, it therefore follows that
hybrid materials based on these components emerge as
interesting candidates to overcome the increasing problem of
bacterial resistance towards conventional antibiotics.[29–32] The
ionic combination of peptides or peptide-polymers and POMs
have resulted in hybrids with better antimicrobial activities than
each component alone.[33–35] In addition, the vast combinatorial
possibilities of both POMs and amino acids means that it is also
possible to tune the secondary structure, molecular weight and
antimicrobial properties of the hybrid.
features needed for
a certain function such as charge,
hydrophilicity/hydrophobicity or secondary structure. Thus, its use
has been explored with different naturally occurring amino acid
monomers and initiators to confer specific functionality and
different chemistries to the peptidic chain.[4–6] In addition to
conventional initiators as organic nucleophiles, several non-
conventional platforms such as gold surfaces or metallic
nanoparticles have been employed as NCA polymerisation
[*]
H. Soria-Carrera, I. Franco-Castillo, Dr. P. Romero, Dr. S. Martín,
Prof. J. M. de la Fuente, Dr. S. G. Mitchell, Dr. R. Martín-Rapún
Instituto de Nanociencia y Materiales de Aragón (INMA)
CSIC-Universidad de Zaragoza
c/ Pedro Cerbuna 12, 50009 Zaragoza (Spain)
E-mail: scott@unizar.es , rmartin@unizar.es
H. Soria-Carrera, I. Franco-Castillo, Prof. J. M. de la Fuente, Dr. S.
G. Mitchell, Dr. R. Martín-Rapún
[b]
CIBER de Bioingeniería, Biomateriales y Nanomedicina
Instituto de Salud Carlos III
28029 Madrid (Spain)
[c]
[d]
Dr. R. Martín-Rapún
Departamento de Química Orgánica, Facultad de Ciencias
Universidad de Zaragoza
c/ Pedro Cerbuna 12, 50009 Zaragoza (Spain)
Dr. S. Martín
Here we present the use of an amino-functionalised Mn-
Anderson-POM as an initiator for the on-POM ROP of amino acid
NCAs. We have termed the hybrid POM-peptides obtained by this
polymerisation approach as POMlymers (Figure 1). In this proof-
of-principle report we combine hydrophobic (Nε-protected lysine)
Departamento de Química Física, Facultad de Ciencias
Universidad de Zaragoza
c/ Pedro Cerbuna 12, 50009 Zaragoza (Spain)
Supporting information containing full characterisation data for this
article is given via a link at the end of the document.
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10.1002/anie.202013563
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COMMUNICATION
and cationic residues (lysine) to explore the antimicrobial and
antibiofilm behaviour of the resulting POMlymers. To the best of
our knowledge, this is the first example of ROP using a molecular
metal-oxide as initiator and inorganic molecular scaffold. From a
fundamental standpoint, this “on-POM polymerisation” strategy
represents a modular and controllable synthetic approach for
producing libraries of POMlymers with controlled molecular
weight and structure, from organo-functionalised POMs and
amino acids. Such an approach could pave the way to next
generation hybrid materials with additive or synergistic
antimicrobial properties.
precipitation in water offered the advantage that TBA cations
could be removed almost completely, which was crucial in order
to perfectly isolate the contributions of the POM against bacteria,
since tetraalkylammonium cations are known antibacterial
agents.[29]
TFA
TFA
Figure 2. Structure of POMK30
and 1H NMR spectrum of POMK30
.
Relevant signals to characterise the structure of the polymers are highlighted
with colour boxes.
Table 1. Characterisation results of POMlymers POMKnTFA and POMKn.
TFA
POMKn
POMKn
Feed[a]
M[b]
[kg/mol]
Ratio[a]
(NMR)
Mn
(NMR)[c]
[kg/mol]
M[d]
[kg/mol]
Mn
(GPC)[e]
[kg/mol]
Ð
(GPC)
TFA
Figure 1. On-POM preparation of POMlymers POMKn
via ring-opening
polymerisation (ROP) of N-carboxyahydride (NCA) and subsequent
deprotection to obtain the positively charged POMlymers POMKn.
ZK NCA and TFAK NCA (Ne-benzyloxycarbonyl and
trifluoroacetamide protected lysine respectively) were selected as
precursor monomers to obtain respectively the hydrophobic and
cationic residues in the final POMlymers, whereas
[MnMo6O18((OCH2)3CNH2)2]3- with tetrabutylamonium (TBA) as
countercations was chosen as bifunctional initiator (Figure 1). To
mimic the favoured structure of an AMP, we randomly
copolymerised both monomers. We anticipated that the higher
number of TFAK residues (lysine residues after deprotection)
would confer a higher degree of antimicrobial activity due to the
increased number of cationic residues. In consequence, we fixed
10:10
30:30
30:90
6.0
1:11:11
1:38:35
1:38:89
6.5
5.1
-
-
15.7
29.2
19.0
31.0
12.9
20.6
21.0
29.3
1.19
1.35
[a] Expressed by the molar ratio POM:ZK:TFAK in the feed and in the polymer
(NMR). [b] As calculated based on the feed but excluding TBA. [c] Calculated
based on the integration of Tris signal at ca. 65 ppm. [d] As calculated based on
the feed but excluding hydrochloride and TBA. [e] Relative to PMMA standards
with HFIP with 3 g L-1 K+TFA− as eluent.
After polymerisation, the composition of the polymeric scaffold
was evaluated using H-NMR on the POMlymers precipitated in
1
the hydrophobic residue content at 30 repeating units and we set
TFA
the TFAK NCA feed to 30 and 90 residues (POMK30
and
diethyl ether (Figure 2 and S8-S10). The ratio between the
comonomers reflected that of the reaction mixture as calculated
from the integration of the proton signals of the trifluoroacetamide
and the benzylic hydrogens of the Z protecting group (Figure 2).
The methylene protons closer to the Mn(III) core in the Tris-
functionalised POM were used to determine the average degree
of polymerisation, which corresponded well with that defined by
the feed (Table 1). Due to the strong paramagnetic behaviour of
Mn(III) the methylene signal is subject to a large downfield
chemical shift and its signal appears at ca. 65 ppm (inset in Figure
2). When precipitated in water instead of diethyl ether, TBA
POMK90TFA). We also prepared a short oligomer containing 10
residues of each monomer, POMK10TFA, to test whether the
solubility would play an important role in the antimicrobial activity
(Figure 1). As control, the synthesis of the polymers KnTFA without
the POM moiety was initiated with n-butylamine. In all cases the
polymerisation was performed following an adapted protocol that
had previously ensured a living chain growth polymerisation with
fast reaction kinetics by removing the CO2 formed during the
reaction.[36,37] All the polymers could be isolated by precipitation in
either water or diethyl ether. In the case of POMlymers,
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cations were mostly removed which led to the disappearance of
the methylene signal at ca. 65 ppm. The suppression of the signal
was probably due to the change in the environment of
paramagnetic Mn(III) ion as well as solvation effects, as it was
recovered after treating the material with a solution of TBA
bromide in diethyl ether (Figure S23).
do not correspond to the peptidic part. (Figures S31-S33). XPS
was used to identify Mn(III) and Mo(VI) in POMKn POMlymers.
Consistent with the DOSY spectra, gel permeation
chromatography traces recorded for POMKn in HFIP with 3 g L-1
K+TFA− showed monomodal distributions for POMlymers
POMK90 and POMK30, with estimated molecular weights similar
to the control polymers K90 and K30. POMK10 exhibited scarce
solubility and therefore its GPC was not measured.
Bearing in mind the importance of conformational structure for
developing materials with antimicrobial properties, we used
circular dichroism (CD) spectroscopy to study the differences in
how the polypeptide sequence folds (in HFIP) when conjugated
to the POM. For the shortest POMlymer (POMK10) we observed
that the metallic centre favoured the folding into α-helices (Figure
3), in turn, its analogue K10 did not show any particular
conformation but random coil (Figure S34). This phenomenon
was already described by Yvon and Ventura et al., for POM and
peptide hybrids prepared by SPPS, but without any further
explanation.[19,39] In contrast, POMK30 and POMK90 adopted a
random coil conformation whereas their POM-free counterparts
K30 and K90 formed α-helices (Figures 3B and S34). Our
Figure 3. A) GPC profiles (UV absorbance at 210 nm) of POMlymers POMK90
and POMK30; B) CD spectra of POMK90, POMK30 and POMK10 as measured in
HFIP (0.1 mg L-1).
The targeted materials (POMKn) were prepared by selective
cleavage of the trifluoroacetamide group under mild alkaline
conditions.[38] The successful cleavage was confirmed by the
disappearance of the –CF3 signal in 19F-NMR (Figure S22). The
materials were insoluble in DMSO and H2O, nevertheless, it was
possible to solubilise them with hexafluoroisopropanol (HFIP),
which is known to favour the dissolution of hydrogen bonded
aggregates. 1H-NMR spectra of POMKn showed only signals
belonging to the polypeptidic chain and side groups while the
methylene signals of Tris ligands were suppressed (Figures S12-
S14). POM decomposition or fragmentation during the
deprotection step would give rise to a broader variety of polymeric
structures with smaller size. In consequence we used DOSY
(Diffusion Ordered SpectroscopY) 1H-NMR as a tool to determine
hypothesis is that POM-free structures possess
a longer
uninterrupted peptide chain, with a larger number of ZK residues
which are known to induce a helical conformation. However, when
the solvent contained 3 g L-1 K+TFA− as used in GPC, α-helices
were detected for all POMlymers POMKn and control polymers Kn,
even for K10 (Figures S35-S36). It therefore follows that K10
should be less prone to adopting the α-helix conformation and
would lead to the coexistence of α-helix and random coil
conformations in HFIP containing 3 g L-1 K+TFA−. This is
translated to an apparent bimodal GPC trace and broader
molecular weight distribution (Table S1 and Figure S30).[40]
Table 2. Surface antimicrobial activity of POMK10 and POMK90 determined
using the Japanese Industrial Standard (JIS Z 2801).
TFA
whether the POM was still attached to the polypeptide. POMKn
and POMKn showed that the presence of the paramagnetic
Mn(III) not only affects the signal of the Tris methylene protons
but also the signals along the polymeric structure, mainly α-
protons: After applying the magnetic field gradients, the
methylene bridges in Tris ligands and the α-proton signals were
Sample
Concentration
[μg cm-2]
Bacterial reduction
[%]
640
160
20
100
100
41
suppressed due to the interaction with the magnetic field. This
POMK10
TFA
effect seems to be more pronounced for POMKn
POMKn. However, in polymers Kn
than for
TFA
and Kn, without POM, we
did not observe this phenomenon, confirming that the
paramagnetic effect is indeed transferred through the peptide
backbone. When comparing DOSY spectra of both POMKn and
Kn polymers we did not observe any significant change on the
pattern of the molecular diffusion (Figure S24-S29), concluding
that the POM was still attached to the polymer in POMKn.
Additionally, the presence of the POM was verified directly by
using a combination of FTIR (Figures S31-S33) and X-ray
Photoelectron Spectroscopy (XPS) (Figures S37-S38). Briefly,
FTIR spectra can be used to prove the presence of Mn-Anderson
[MnMo6O18((OCH2)3CNH2)2]3- in the final POMKn materials. The
Mo=O and Mo–O stretches (ca. 890 cm-1 and 690 cm-1,
respectively) are present for MnMo6 Mn-Anderson starting
material and POMKn. These bands are absent in Kn, which do not
contain the MnMo6 Mn-Anderson, showing that the bands in the
1200-600 cm-1 region of the spectra in the final POMKn materials
640
160
20
100
100
100
POMK90
[a] Refer to Figure S43 for full log(CFU) reduction data.
The presence of poly(lysine) combined with the limited
aqueous solubility make POMlymers interesting candidates for
antimicrobial surface coatings to prevent biofilm formation.[25,41]
Bacteria that attach to a surface or to an interface can grow as a
densely packed multicellular community of microorganisms, a
biofilm, that protect them from the bactericidal effects of different
antimicrobials, such as antibiotics. Biofilms are the source of
persistent infections of many pathogenic microbes. The
POMlymers in this report were evaluated against the Gram-
positive Bacillus subtilis, which is a widely studied non-pathogenic
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biofilm model.[42,43] Colorimetric cell viability assays were used to
determine the bactericidal activity of the POMlymers (expressed
as the concentration of the POMlymer per cm2). The bactericidal
activity of POMK90 against B. subtilis corresponded to 31.2 μg cm-
2, while the bactericidal concentration of POMK10 was 500 μg cm-
2 (Figure S39). As control experiments, we also evaluated each
counterpart individually and the combination of Kn with
Na3[MnMo6O18((OCH2)3CNH2)2][44] (Figures S40-S42). All
antibacterial results are summarized in Table S2.
The surface antibacterial activity was also confirmed using a
modified Japanese Industrial Standard (JIS Z 2801), which
verified that POMK90 provided a complete bacterial cell viability
reduction on surfaces at concentrations as low as 20 μg cm-2
(Table 2). POMK10 provided surface bactericidal action at
concentrations of 640 and 160 μg cm-2 while at lower
concentrations of 20 μg cm-2 the bacterial reduction was
determined to be 41 % (please also refer to Figure S43 for
log(CFU) reduction data).
the POMlymers) showed how B. subtilis colonised the non-coated
sample and developed a biofilm, while the coated samples fully
inhibit biofilm development (Figure 4). Both POMK10 and POMK90
fully protect from B. subtilis surface colonisation; however, some
bacteria aggregates were observed in the 20 μg cm-2 POMK10
sample, commensurate with the antimicrobial results (Figure S43).
A Crystal Violet assay, on the other hand, was used to evaluate
the ability of the bacteria to develop a pellicle biofilm at the liquid-
air interface. Spectrophotometric analysis of the intensity of the
biofilm halo developed at the liquid-air interface demonstrated
that both POMK90 and POMK10 inhibit biofilm formation at
concentrations as low as 160 μg cm-2 (Figure S44).
In this work we have demonstrated how hybrid POM-
materials can be accessed through ring opening polymerisation
(ROP) of N-carboxyanhydrides (NCAs) where the POM serves as
the molecular metal-oxide scaffold initiator. We have designated
the hybrid POM-peptides prepared using this approach as
POMlymers. Here we have shown how a series of poly(lysine)-
functionalised POMs were prepared under living polymerisation
conditions by varying the number of cationic residues and the
length of the polymer and that after the deprotection step in basic
medium, the integrity of the POM is preserved. Some of these
bactericidal POMlymers possessed surface antibacterial activity
at concentrations as low as 20 μg cm-2 (POMK90), which
completely prevented biofilm growth. The POMK90 POMlymer
serves as a promising proof-of-concept candidate whose design
could be improved to develop alternative antimicrobial hybrids to
tackle biofilms that provide highly protective environments for
pathogenic bacteria. In summary, the “on-POM polymerisation”
represents a new design principle towards hybrid materials and a
versatile route to produce POMlymers for combating biofilms that
are highly resistant to conventional therapies.
Acknowledgements
Financial support from Ministerio de Ciencia Innovación y
Universidades (Spain) through a Ramón y Cajal fellowship (RMR,
RYC-2013-12570) and Proyectos I+D+i (PID2019-109333RB-I00,
PGC2018-097583-B-I00, and PID2019-105881RB-I00) and CSIC
i-Link+2019 project (LINK20270). HSC and IFC are grateful for
predoctoral fellowships from Ministerio de Educación Cultura y
Deporte (FPU program) and Gobierno de Aragón, respectively.
Further financial support from Fondo Social Europeo-Gobierno de
Aragón (E15_20R, E47_20R and LMP33-18) and CIBER-BBN is
gratefully acknowledged. The authors would like to acknowledge
the Laboratorio de Microscopias Avanzadas (LMA) at Universidad
de Zaragoza for offering access to their instruments and expertise,
especially Guillermo Antorrena for the XPS measurements; the
use of the Unidad de Apoyo a la Investigación del CEQMA (CSIC-
Universidad de Zaragoza). The authors also thank Dr. Elena
Atrián-Blasco for fruitful discussions.
Figure 4. Environmental Scanning Electron Microscopy (ESEM) images of B.
subtilis incubated over a silicon wafer coated with POMK10 and POMK90 at 20
and 640 μg cm-2 (and over a non-coated sample as a biofilm positive control).
Bacteria incubated over the non-coated sample are covering the surface by
developing a biofilm. Some bacterial aggregates in the sample coated with 20
μg cm-2 POMK10, but at the highest concentration (640 μg cm-2) no bacteria were
observed. Surfaces coated with 20 or 640 μg cm-2 POMK90 show no biofilm
growth.
Keywords: Polypeptides • Polyoxometalates • Ring Opening
Polymerisation • Antimicrobial activity • Biofilm
The biofilm prevention properties of the POMlymers were also
studied by Environmental Scanning Electron Microscopy (ESEM)
and by Crystal Violet assays. The ESEM analysis of the biofilm
growth over silicon wafers (coated with different concentrations of
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10.1002/anie.202013563
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COMMUNICATION
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10.1002/anie.202013563
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
"On-POM polymerisation": An amino-
functionalised Polyoxometalate (POM)
as initiator for the ring-opening
polymerisation (ROP) of α-amino acid
N-carboxyanhydrides (NCAs) under
living polymerisation conditions. The
resulting POM-peptide materials
(POMlymers) possess bactericidal
properties and prevent biofilm
formation.
Héctor Soria-Carrera, Isabel Franco-
Castillo, Pilar Romero, Santiago Martín,
Jesús M. de la Fuente, Scott G.
Mitchell,* Rafael Martín-Rapún*
Page No. – Page No.
On-POM ring-opening polymerisation
of N-Carboxyanhydrides
This article is protected by copyright. All rights reserved.