1,2,3-Triazolium-Based Cationic Amphipathic Peptoid Oligomers Mimicking Antimicrobial Helical Peptides

Article abstract of DOI:10.1002/cmdc.201800273

Amphipathic cationic peptoids (N-substituted glycine oligomers) represent a promising class of antimicrobial peptide mimics. The aim of this study is to explore the potential of the triazolium group as a cationic moiety and helix inducer to develop potent antimicrobial helical peptoids. Herein we report the first solid-phase synthesis of peptoid oligomers incorporating 1,2,3-triazolium-type side chains and their evaluation against Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus. Several triazolium-based oligomers, even of short length, selectively kill bacteria over mammalian cells. SEM visualization of S. aureus cells treated with a dodecamer and a hexamer reveals severe cell membrane damage and suggests that the longer oligomer acts by pore formation.

Full text of DOI:10.1002/cmdc.201800273

Accepted Article
Title: 1,2,3-Triazolium-based cationic amphipathic peptoid oligomers
mimicking antimicrobial helical peptides
Authors: Radhe Shyam, Nicolas Charbonnel, Aurélie Job, Christelle
Blavignac, Christiane Forestier, Claude Taillefumier, and
sophie Faure
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ChemMedChem
10.1002/cmdc.201800273
COMMUNICATION
1,2,3-Triazolium-based cationic amphipathic peptoid oligomers
mimicking antimicrobial helical peptides
[
a]
[b]
[a]
[c]
Dr. Radhe Shyam, Nicolas Charbonnel, Aurélie Job, Christelle Blavignac, Prof. Dr. Christiane
[b]
[a]
[a]
Forestier, Prof. Dr. Claude Taillefumier and Dr. Sophie Faure*
[a]
Dr. R. Shyam, A. Job, Prof. C. Taillefumier, 0000-0003-3126-495X, Dr. S. Faure, 0000-0001-5033-9481
Université Clermont Auvergne, CNRS, SIGMA Clermont, ICCF, F-63000 Clermont−Ferrand, France
E-mail:sophie.faure@uca.fr
[
b]
c]
N. Charbonnel, Prof. C. Forestier
Université Clermont Auvergne, CNRS, LMGE, F-63000 Clermont−Ferrand, France
C. Blavignac
[
Université Clermont Auvergne, Centre Imagerie Cellulaire Santé, F-63000 Clermont−Ferrand, France
Supporting information for this article is given via a link at the end of the document.
Abstract: Amphipathic cationic peptoids (N-substituted glycine
oligomers) represent a promising class of antimicrobial peptide
mimics. The aim of this study is to explore the potential of the
triazolium group as a cationic moiety and helix inducer to develop
potent antimicrobial helical peptoids. We report here the first solid-
phase synthesis of peptoid oligomers incorporating 1,2,3-triazolium-
type side chains, and their evaluation against Escherichia coli,
Enterococcus faecalis and Staphylococcus aureus. Several
triazolium-based oligomers, even of short length, selectively kill
bacteria over mammalian cells. SEM visualization of S. aureus cells
treated with a dodecamer and a hexamer reveals severe cell
membrane damages and suggests that the longer oligomer acts by
pore formation.
Figure 1.a) Generic structure of cationic amphiphilic peptoids; Side chain
structure of N-glycine residues: b) Nspe for (S)-N-(1-phenylethyl)glycine; c)
NLys
forN-(4-aminobutyl)glycine;
d)
Nchtmfor
Naetm
Nbtm
for
N-(1-benzyl-1,2,3-
The increasing emergence of multidrug-resistant pathogenic
bacterial strains has let to intense research on alternative
strategies to overcome microbial infections. Part of the innate
immune system, antimicrobial peptides (AMPs) have gained
increased attention due to their broad spectrum activity against
triazolylmethyl)glycine,
triazolylmethyl)glycine
triazolylmethyl)glycine; e) Nbtm for N-(1-benzyl-3-methyl-1,2,3-triazolium
methyl)glycine, Nchtm for N-(1-cyclohexylmethyl-3-methyl-1,2,3-triazolium
methyl)glycine andNaetm for N-(1-(2-aminoethyl)-3-methyl-1,2,3-triazolium
N-(1-cyclohexylmethyl-1,2,3-
for N-(1-(2-aminoethyl)-1,2,3-
and
+
+
+
methyl)glycine.
[1]
bacteria, fungi and parasites. Besides, their main mechanism
of action by bacterial cell membrane disruption implies low
emergence of resistance. However their exploitation as
therapeutics was hampered by unsuitable toxicity and
influence on activities (oligomer length, charge, hydrophobicity,
chirality, secondary structure and side chain nature), the mode
of action of these peptidomimetics and their selectivity for
bacteria vs mammalian cells have been scrutinized over the last
ten years.
predict potency of designed linear peptoids.
been shown to increase the membrane activity resulting in
[2]
pharmacokinetics. Peptidomimetics exhibiting the mechanism
of action of AMPs with enhanced proteolytic stability have been
[3]
[6,10]
widely explored during the last decade.
Many of these
A number of descriptors have been identified to
[11]
mimetics have been designed to exhibit the cationic amphipathic
helical structure of native AMPs, which is the key determinant of
Cyclisation has
[4]
[
12]
their activity. Among them, peptoids (N-substituted glycine
superior in vitro bacterial growth inhibition.
Despite the huge
[
5]
[4e,
oligomers) represent a promising class of AMP mimics.
number of amphipathic cationic peptoid oligomers studied, the
chemical diversity of the cationic pendant groups is limited to
date to positively charged proteinogenic side chain equivalents
i.e. ammonium, guanidinium, and imidazolium moieties. These
side chains bring the positive charge but do not exert any role on
the folding into amphipathic helix. The use of cationic side chain
involved in the stabilization of the helix may provide short
amphiphilic oligomers with interesting antimicrobial properties.
The PPI-like helix can be generated using side chains which
stabilize the cis conformation of the backbone amides through
6
]
Peptoids possess desirable advantages such as protease
stability, cost-effective synthesis, and a great potential for
[
7]
diversity.
periodicity of the polyproline type-I -like helix (PPI) of -
[4e]
The Barron group showed that the threefold
[
8]
peptoids enabled mimicry of the magainin helical structure.
The amphipathic helix was built by periodic incorporation of a
cationic side chain every three residues, the remaining positions
being occupied by the aromatic -chiral (S)-phenylethyl side
chain which helps the formation of helix and provides
hydrophobic helical faces (Figure 1a,b,c). The dodecamer
[8,13]
steric and/or electronic interactions.
The 1,2,3-triazolium-
(
NLys-Nspe-Nspe)
4
showed
excellent
broad
spectrum
type side chain exhibits a strong cis-directing effect thanks to an
efficient n→*Ar electronic interaction. This positively-charged
side chain should enable to target bacterial membrane while
[14]
antibacterial activities, but also displayed potent cytotoxicity
towards carcinoma cells. Parameters that may have an
[9]
1
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ChemMedChem
10.1002/cmdc.201800273
COMMUNICATION
promoting helical folding of peptoid oligomer. 1,2,3-Triazolium
salts have been extensively studied for application as ionic
liquids, catalysts or receptors but their implication in substances
of biological interest was by far less explored than its 1,2,3-
[15]
triazole parent.
In this communication, we report on the synthesis and the
evaluation of peptoids incorporating triazolium-type side chains
(
Figure 1). Our aim was to explore the potential of the triazolium
as cationic pendant group and structuring element to develop
potent AMP mimetics. Based on the rational design of
[4e,6]
amphipathic cationic peptoid structure,
oligomers comprising
trimer repeats with two consecutive bulky -chiral spe side
chains and one cationic 1,2,3-triazolium-type side chain were
designed. The best way for the multivalent formation of 1,2,3-
triazolium groups was initially assessed by synthesising the
+
model hexamer H-(Nchtm -Nspe-Nspe)
2
-NH
2
3 in solution or on
support (Scheme 1).
Scheme 1.Synthetic access to 1,2,3-triazolium-based model hexamer 3. Key:
First, peptoid 1 carrying site-specifically located spe side chains
and propargyl side chains (em) as triazolium precursors,
wasprepared by standard microwave-assisted solid-phase
(a) TFA/TIS/H O; (b) cyclohexylmethyl azide, CuSO4, ascorbic acid,
H O/tBuOH, 12h; (c) MeI, CH CN, 70°C; (d) cyclohexylmethyl azide, CuI,
2 3
DIPEA, ascorbic acid, DMF/pyridine, 18h; (e) MeI, 45°C; Abbreviations: Nem
for N-(ethynylmethyl)glycine.
2
[6]
submonomer strategy.
achieved by using
Triazole formation in solution was
standard Cu-Catalysed Azide-Alkyne
a
(
CuAAC) reaction protocol. Using cyclohexylmethyl azide, the
solvents and at different temperature. Most of the time, only one
methylation occurred providing a complex mixture of compounds.
Complete conversion of triazole into triazolium was finally
achieved by exposing the resin to pure methyl iodide at 45°C
during 5h. Then, hexapeptoid 3 was cleaved from support and
efficiently obtained. Using this approach, three series of
oligomers were generated with various substituents on
triazole/triazolium: an aminoethyl, a cyclohexylmethyl and a
benzyl for series A, B and C, respectively (Table 1 and ESI for
details). This library includes oligomers with a sequence length
of 6, 9 and 12 residues and an overall positive charge ranging
from 0 to +8.
conversion of the alkynyl functions into triazolyl was achieved,
yielding hexapeptoid 2 in 52% yield. Conversion of the triazoles
into triazoliums was tested using a well-established protocol
[16]
(
Scheme 1). A complex mixture of compounds was obtained
likely due to the presence of the primary amide and the
unprotected terminal-amine group. This result prompted us to
develop a new strategy consisting in forming the triazolium
moiety directly on the resin after a prerequisite protection of the
N-terminal amine. Therefore, the supported peptoid res-1 was
protected with a Boc group, sensitive to the resin cleavage
conditions. The multiple CuAAC reaction was then performed on
supported peptoid res-4 using copper iodide, Hünig’s base and
The antibacterial activity of the designed amphiphiles was
assessed against both Gram-negative bacteria (two strains of
Escherichia coli) and Gram-positive bacteria (Enterococcus
[17]
ascorbic acid. Thereafter, triazolium formation was studied on
support. On the basis of previous work, methyl iodide was
chosen as alkylating reagent at various concentrations in diverse
Table 1. Antibacterial activities and selectivity of triazole- and triazolium-based cationic amphipathic peptoids.
[a]
[b]
[c]
[d]
[e]
Series/Nbr
Peptoid sequence
MW
charge
MIC [M]
HC10/HC50
CV
SR
[
M]
(%)
E. coli*
E. coli** E. faecalis
S. aureus
-
6
6
6
ref
A/5
A/6
A/7
A/8
B/2
B/3
B/9
C/10
H-(NLys-Nspe-Nspe)
4
-NH
2
1819
1249
1864
2480
2031
1130
1355
2023
2053
2847
4
4
6
8
4
0
2
3
3
6
3.5
14-24
>200.0
100.0
50.0
-
21/100
-
-
-
-
+
H-(Naetm -Nspe-Nspe)
2
-NH
3
-NH
4
-NH
2
2
2
>200.0
25.0
>200.0
50.0
>200.0
50.0
-
+
H-(Naetm -Nspe-Nspe)
>200/>200
100±9.2
>4
+
H-(Naetm -Nspe-Nspe)
11.5±1.0
6.3
6.3
6.3
>200/>200 100±11.8 >31
H-(Naetm-Nspe-Nspe)
4
-NH
2
12.5
11.5±1.0
> 200.0
6.3
10.4±1.3
> 200.0
3.1
>100/>200
-
6±6.3
-
>9
-
H-(Nchtm-Nspe-Nspe)
2
-NH
2
> 200.0
50.0
> 200.0
50.0
+
H-(Nchtm -Nspe-Nspe)
2
3
-NH
2
2
>200/>200
50/>75
>50/>100
100±9.8
7±6.0
7±5.9
-
>64
31
>31
-
+
H-(Nchtm -Nspe-Nspe)
-NH
25.0
25.0
1.8±0.3
1.6
1.6
+
H-(Nbtm -Nspe-Nspe)
3
-NH
2
12.5
12.5
1.6
[f]
18
19
19
20
Melittin
6.3(4-16)
6.3
6.3(1-8)
3.1(0.5-4)
-/7
[a] Molecular weight including triazolium counterions. [b] Minimum inhibitory concentration (MIC) was determined as the lowest concentration of peptide that
inhibited bacteria growth of Escherichia coli *JM109 and **ATCC® 25922™, Enterococcus faecalis ATCC® 29212™, Staphylococcus aureus CIP 6525. A
minimum of three independent experiments of the assay were conducted, and two technical replicates were used in each experiment for each bacterium, peptoid
and concentration. [c] Haemolytic concentrations at which 10% and 50% haemolysis are observed. Assays were performed in triplicates. [d] Cell viability (CV):
average percentage of viable HeLa cells after peptoid exposition at 100 M during 24h (MTT assay). Data are presented as the means ±SEM of three
independent experiments. [e] Selectivity ratio SR
=
HC10/MICS.aureus
;
[f] Honey bee peptide GIGAVLKVLTTGLPALISWIKRKRQQ
…
2
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ChemMedChem
10.1002/cmdc.201800273
COMMUNICATION
faecalis and Staphylococcus aureus) (Table 1). Selectivity for
bacterial over mammalian cells was assessed by testing the
haemolytic activities on human red blood cells (hRBC) and the
toxicity on HeLa cell. In the series A, antimicrobial potency
exponentially increased with oligomer length as usually
The lengthened peptoid 9 showed a two- or three-fold decrease
in the MIC value for all bacteria. Regrettably, this nonamer
proved more haemolytic (HC10 50 M) than the hexamer 3 but
the selectivity ratio remained very acceptable. Lastly, the
influence of additional aromatic group was studied by
comparison of nonamers 9 and 10. It is usually noticed in AMP
mimetics design that hydrophobic aromatic groups help at
improving antibacterial activity but were often detrimental to the
[6,10]
observed for cationic amphiphilic peptoids.
The hexamer 5
has no effect on bacterial strains whereas the dodecamer 7
exhibits high antibacterial activities particularly on Gram-positive
bacteria. In contrast with previous studies, no increase of
haemolytic activity was observed for longer oligomers (6 versus
[4,6,10]
specificity.
The nonamer 10 exhibits the best activities over
the panel of bacterial strains studied and was surprisingly
slightly less haemolytic than nonamer 9 with a selectivity ratio
SR greater than 31.
7
). By contrast with the triazolium, the triazole may not exert any
marked influence on the peptoid main-chain for adoption of a
PPI-like helical conformation. However, the dodecamer
8
As for AMPs, studies have provided evidence that amphipathic
[
6,12b,22]
bearing uncharged triazole moieties, was found to have a broad
spectrum activity with potency similar to that of the reference
cationic peptoids act by bacterial membrane disruption,
[18c,23]
however additional modes of action are not excluded.
[6]
sequence against E. coli. Accordingly, in this first series, the
incorporation of a triazolium group in between the peptoid
backbone and the ammonium cationic moiety did not show any
beneficial effect on the MIC values. But these triazolium-based
peptoids were less haemolytic and toxic than their triazole
precursors and the reference sequence (7 versus 8 and ref). In
the series B and C, the net positive charge of the oligomers
arises exclusively from the triazolium groups. As expected
compound 2 with the uncharged triazoles was inactive on
bacteria. However, quaternisation of the two triazoles resulted in
the cationic amphiphile 3 with unprecedented antibacterial
activities for a linear peptoid of this length. Indeed, MIC of 6.3
and 3.1 M were measured against E. faecalis and S. aureus,
respectively. It is important to note that in the course of
antimicrobial peptoids design, short oligomers were often poorly
active except those incorporating the dehydroabietyl moiety or a
Changes in membrane morphology of S. aureus bacteria upon
treatment with dodecamer 7, the longest peptoid from the A
series and the short hexamer 3 from the B series, were
visualized using Scanning Electron Microscopy (Figure 3).
A
B
C
D
[
21]
long alkyl tail.
The potency of peptoid 3 may be due to the
[14,16]
structuring effect of the triazolium.
Preliminary CD study on
this series showed that peptoids 2, 3 and 9 present the
characteristic CD signature of the PPI-like helix of peptoids with
[
8]
two minima at 203 and 220 nm (Figure 2). The lower band
intensity for triazole-based hexapeptoid 2 compared to the
triazolium-based hexapeptoid 3 is indicative of the helical
structure stabilisation by the triazoliums. Besides, a similar CD
signature was observed for the hexamer 3 and the nonamer 9
suggesting that the short oligomer has already good helical
integrity which may explain its good activity.
E
8
Figure 3. SEM micrographs of S. Aureus cells A) Cultures in log phase at 10
CFU/ml at T = 0; B) untreated after 18h; C) treated with the dodecamer 7 at
the MIC (6.3 M) after 18h; D) treated with the hexamer 3 at the MIC (3.1 M)
after 18h; E) Field emission gun SEM of S. Aureus cells treated with the
dodecamer 7 at the MIC (6.3 M) after 18h.
In the control samples (untreated S. aureus), the cells appeared
with round and smooth surfaces in grape-like clusters (Figure
3
A,B). Upon treatment with the peptoid
cytoplasmic leakage and membrane damage were observed
Figure 3C,E). Cells showed surface depressions and some of
7 at the MIC,
(
them had holes (≈ 70-80 nm diameter) in their cell wall. Pore
formation has been previously observed on MRSA membrane
[12b]
treated with cyclic peptoids.
SEM micrographs of bacteria
treated with the hexamer 3 at the MIC showed significant
morphological alterations such as membrane corrugation, but no
pores have been detected (Figure 3 D).
In this study, three series of 1,2,3-triazolium-based cationic
amphipathic peptoid oligomers have been efficiently synthesized
on support. Among them, nonamers 9 and 10 showed potent
activities (MIC ≤ 3 M) especially against E. faecalis and S.
Figure 2.Circular dichroism (CD) spectra of series B oligomers at 500 M in
MeOH.
3
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ChemMedChem
10.1002/cmdc.201800273
COMMUNICATION
aureus strains, and good selectivity. Besides, the short hexamer
Liu, Z. Miao, M. Park, Y. Wang ,T. M. Miller, A. E. Barron; Z. Cheng,
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3
was also active against Gram-positive bacteria and absolutely
non-haemolytic and non-cytotoxic on Hela cells. SEM
visualization of S. aureus cells treated with peptoids 3 or 7
revealed severe cell membrane damages. Our observations
suggest that the longest peptoid 7 acts by pore formation while
the hexamer 3 seems to cause membrane permeation by
another mechanism. This work highlights the potential of
triazolium-based cationic amphipathic peptoids for the
development of selective antimicrobial agents. Further studies
will be conducted to improve their potency and to better
understand their mechanism of action.
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ChemMedChem
10.1002/cmdc.201800273
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Triazolium as cationic pendant group and helix inducer: Rapidly and efficiently synthesized on solid-phase, amphipathic
helicalpeptoid oligomers incorporating 1,2,3-triazolium-type side chain as a cationic moiety and structuring element, were evaluated
against Escherichia coli, Enterococcus faecalis and Staphylococcus aureus. These amphipathic oligomers, even of short length,
selectively kill bacteria over mammalian cells.
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