New antimicrobial self-assembling short lipopeptides

Article abstract of DOI:10.1039/d1ob01227d

Lipopeptides are an exceptional example of amphiphilic molecules that self-assemble into functional structures with applications in the areas of nanotechnology, catalysis or medicinal chemistry. Herein, we report a library of 21 short lipopeptides, together with their supramolecular characterization and antimicrobial activity against both Gram-negative (E. coli) and Gram-positive (S. aureus) strains. This study shows that simple lipoamino acids self-assemble into micellar or vesicular structures, while incorporating dipeptides capable of stablishing hydrogen bonds results in the adoption of advanced fibrilar structures. The self-assembly effect has proven to be key to achieve antimicrobial activity.

Full text of DOI:10.1039/d1ob01227d

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New antimicrobial self-assembling short
lipopeptides†
César Vicente-García a and Ignacio Colomer
Cite this: Org. Biomol. Chem., 2021,
19, 6797
a,b
*
Received 24th June 2021,
Accepted 16th July 2021
DOI: 10.1039/d1ob01227d
rsc.li/obc
Lipopeptides are an exceptional example of amphiphilic molecules
Lipopeptides have been widely used as surfactants and
that self-assemble into functional structures with applications in low-molecular weight gelators.4 Alternatively, extensive
the areas of nanotechnology, catalysis or medicinal chemistry. investigations have shed light on how to control the supra-
Herein, we report a library of 21 short lipopeptides, together with molecular properties by tuning the structural motifs of the
their supramolecular characterization and antimicrobial activity amphiphilic monomers, using α- or β-amino acids,5 homo-
against both Gram-negative (E. coli) and Gram-positive (S. aureus) chiral vs. heterochiral polymers6 or the nature and length of
strains. This study shows that simple lipoamino acids self-assemble the hydrophobic component.7 Moreover, the influence of
into micellar or vesicular structures, while incorporating dipeptides external stimuli on both the self-assembly and the pro-
capable of stablishing hydrogen bonds results in the adoption of perties displayed has been investigated, including concen-
advanced fibrilar structures. The self-assembly effect has proven to tration,8 solvent,9 saline10 or the pH effect.11 Their ability
be key to achieve antimicrobial activity.
to respond to these stimuli and adapt over time has been
used to design synthetic advanced dynamic supramolecular
systems,12 nanostructured materials,13 and self-responsive
delivery systems in the area of medical biotechnology14 or
systems chemistry.15
Although great advances have been made in peptide engin-
eering, identifying small (lipo)peptides with defined supramo-
lecular behaviour,16 catalytic properties17 or biological
activity18 is still a challenge. In this study, we aim to build a
library of small lipopeptides to systematically explore the
chemical space, covering different amino acids, complemen-
tary amino acid sequences, the number and length of the
hydrophobic aliphatic chain, as well as the influence of its
Peptide nanotechnology has emerged as a powerful tool that
allows for the rational design of functional structures whose
supramolecular properties can be engineered and controlled
by manipulating the peptide sequence.1 Amphiphilic peptides
represent a heterogeneous category of these biomolecules that
can be constituted of all amino acids, with alternating hydro-
philic and lipophilic monomers, or that can incorporate
appendant hydrophilic or hydrophobic chains. These amphi-
philes self-assemble into miscellaneous supramolecular struc-
tures (i.e. micelles, vesicles, nanotubes, fibres, nanobelts) exhi-
biting versatile properties and applications.2 Lipopeptides are
a particular example of self-assembling amphiphilic peptides,
formed with a polar hydrophilic head and a long hydrophobic
chain that can be attached either to the N-terminus position
(i.e. fatty acyl moiety, Fig. 1a) or at the C-terminus site (i.e.
fatty amine or alcohol, Fig. 1b). Their self-organization is
highly determined by the sequence of amino acids, something
that prompted rational design to achieve advanced perform-
ances, controlling their morphology and activity, a field that
has rapidly grown in recent years.3
aIMDEA Nanociencia, Faraday 9, Campus UAM, 28049 Madrid, Spain
bInstituto de Química Orgánica General (IQOG-CSIC), Juan de la Cierva 3,
28006 Madrid, Spain. E-mail: colomer@iqog.csic.es
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, chemical and supramolecular characterization and antimicrobial
assays. See DOI: 10.1039/d1ob01227d
Fig. 1 Importance and uses of lipopeptides.
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position (N- vs. C-terminus). Moreover, their biological activity 1j.20 Aiming to increase the structural complexity that would
will be investigated, in particular as antimicrobial agents. allow for additional non-covalent interactions, we prepared a
We began our study by preparing lipoamino acids (Fig. 2a) set of lipodipeptides. We decided to focus on Ser and His for
derived from amino acids with variable side chains, bearing their potential H-bonding capabilities, acid–base properties
no substitution (glycine, 1a), and aliphatic (alanine, 1b and and π–π stacking. Using lipoamino acids derived from Ser or
valine, 1c), aromatic (phenylalanine, 1d), hydrogen bond His (1e–h), the complementary amino acid (Ser or His) was
donor (serine, 1e and 1g), pH responsive (histidine, 1f and 1h) coupled at the C-terminus position, leading to four new lipodi-
and redox active (cysteine, 1i–k) functional groups, following peptides (Fig. 2a, 2a–d). The examples described, so far,
the Schotten–Baumann procedure, using free amino acids and display a fatty acyl moiety at the N-terminus position. Thus, we
decanoyl or oleoyl chlorides under basic conditions.19 thought that evaluating complementary C-terminus derivatives
Selective monofunctionalization of cysteine, 1i–j, was achieved will enrich the outcome of this library. A set of six new lipopep-
using benzotriazole to activate decanoic acid, leading to amide tides 3a–f (Fig. 2b) could be accessed using fatty amines. For
1i using a basic medium and a short reaction time (2 h), while the Ser-His sequence, semi-protected common precursor 4
using neutral pH and a longer time (12 h) afforded thioester (ESI†) was reacted with decylamine (3a), oleylamine (3b) or bis-
Fig. 2 Library of lipopeptides synthesized, composed of: (a) N-terminus fatty acyl derivatives and (b) C-terminus fatty amides.
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Table 1 Supramolecular characterization of lipopeptides
oleate amine derived from serinol (3c). For His-Ser derivatives,
an alternative route was needed: first incorporating the fatty
amine into the C-terminus amino acid (Ser) providing serine
amides 5a–c (Fig. 2b), followed by coupling of the N-terminus
amino acid (His) to afford three new lipodipeptides, 3d–f.
With these lipopeptides in hand, we first studied their self-
assembling behavior by performing systematic characteriz-
ation of their supramolecular properties. For every species, we
have determined the minimal concentration needed for them
to aggregate, which is the Critical Aggregation Concentration
(CAC). We have also investigated the particle size of the supra-
molecular assemblies, as well as their stability in solution.
Finally, we have conducted the study of the morphology of
these supramolecular aggregates using electron microscopy.
The supramolecular characterization was started by deter-
mining the CAC, using an established spectrofluorimetric
method (see the ESI†). A representative example for 1f is pre-
sented in Fig. 3A. The CAC for lipoamino acids is in the range
of 0.20–25.0 mM (Table 1), in agreement with the previous
examples reported (see the ESI†). The lowest values of the CAC
were observed for cysteine derivatives (1i–k). For lipodipep-
tides, the CAC data were more disperse (0.01–68.4 mM), with
N-terminus acyl derivatives (2a–d) presenting much lower CAC
than C-terminus fatty amides (3a–f). In general, lipoamino
acids with non-polar side chains (1a–d) exhibit higher CAC
Sizea (nm)
Number
Compound
CAC (mM)
Intensity
ZPa (mV)
1a
1b
1c
1d
1e
1f
1g
1h
1i
25.0
4.50
12.0
12.5
8.90
9.90
6.50
7.60
0.20
3.00
0.70
18
3
4
24, 142
4, 161
5, 196
74, 241
30, 164
35, 120
13, 68
39, 215
15, 95
15, 210
105
—
−65.9
−60.0
−68.5
−85.3
−62.3
−75.3
−60.1
−67.3
—
68
28
32
31
37
10
68
28
1j
1k
−74.2
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
0.01
0.06
5.96
0.01
68.4
45.7
—
8.88
7.17
—
10
37
10
190
68
6
32
28
5
22, 255
40, 220
21, 181
8, 54, 278
70, 137
32, 236
7, 190
30, 130
24, 142
4, 161
+42.2
+69.9
+54.0
+55.9
+61.3
+66.7
+91.2
+21.6
+43.3
+78.3
68
a Data collected at pH 11 for 1a–k and at pH 6 for 2a–d and 3a–f.
values than examples bearing polar side chains capable of about the different populations typically observed in this type
establishing additional non-covalent interactions. This reflects of sample. A representative example for 1f is shown in Fig. 3B,
the well-known influence of the hydrogen bonding capacity initially screening the effect of pH, where basic pH provided
and HLB to enhance the formation of supramolecular struc- monodisperse nanoparticles with an average diameter of
tures.21 Additionally, lipopeptides bearing longer aliphatic 32 nm (see the ESI† for a detailed study); however, below pH 5,
chains display lower CAC than their shorter counterparts, a the supramolecular species starts disassembling and precipi-
trend extensively reported for similar lipopeptides.22
tating. Small particles in the range of 3–68 nm were generally
Using Dynamic Light Scattering (DLS), we then moved to detected for the remaining lipopeptides (Table 1, size by
study the particle size, both by number and intensity to deter- number), together with some larger aggregates in the range of
mine the probable polydispersity and to gain information 105–278 nm, in different ratios depending on the example
(Table 1, size by intensity). For every sample, we observed
exceptionally good raw correlation data (see the ESI†), with a
general trend: small structures identified as micelles
(3–37 nm, size by number) coexist, in some cases, with larger
populations (68–278 nm, size by intensity). DLS is a powerful
and non-invasive technique that works particularly well for
uniform, symmetric and spherical nanoparticles and allows
for studying the particle size both by number and intensity.
While size by intensity constitutes a general overview of the
size from all particle populations, size by number refers to
smaller and more abundant particle populations and should
be taken into account with good correlation functions, as is
the case here.
The stability of these nanoparticles was studied by measur-
ing the magnitude of the zeta-potential (ZP). A representative
study for 1f is shown in Fig. 3C, with very stable particles
above neutral pH, displaying a large absolute value of ZP
(>50 mV), while they are much less stable (<30 mV) below
neutral pH. Under optimal conditions of pH, a large absolute
Fig. 3 Supramolecular characterization of 1f, including (A) critical
magnitude of ZP above 60 mV is obtained in most cases
aggregation concentration, (B) particle size using DLS and (C) self-
assembly stability via zeta-potential analysis.
(Table 1). For lipoamino acids, 1a–k, a large negative ZP would
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agree with a deprotonated carboxylate, as a result of the basic tures observed in the HR-TEM images, which might imply a
pH used. In sharp contrast, for lipodipeptides, 2a–d and 3a–f, hierarchical organization.
measured at neutral pH, a positive value of ZP is observed,
Altogether, moving from simple amino acids to dipeptides
pointing towards a net positive charge, suggesting that this pH incorporating functional groups promoting non-covalent inter-
is below the isoelectric point. Overall, the ZP values for this actions allows for switching the supramolecular structure from
library of lipopeptides demonstrate a general and exceptionally simple micelles to more complex vesicles or fibers (Fig. 5).
good stability (ZP > |40| mV).
Moreover, the size and the presence of a double bond in the
In an effort to improve this study, our attention was driven aliphatic chain play a key role in the development of a more
to study the infrared spectra of these lipopeptides, which complex pattern of self-assembly (compare 2b and 2d vs. 2a
exhibited the following interesting characteristics: (1) red-shift- and 2c). However, the sequence of amino acids can have a pro-
ing of O–H and N–H stretching (from 3500–3000 cm−1 to found effect on the morphology (from vesicles to fibers),
3300–2500 cm−1) and (2) band-reshaping, from smooth bell- which cannot be anticipated, by simply reversing Ser and His
shaped bands to speckled discrete peaks, typical of medium- residues (compare 2b vs. 2d).
to-strong hydrogen bond networks.23 Such spectral character-
One of the biggest challenges concerning public health is
istics provide insight into the overall ability of this pool of lipo- the emergence of multidrug resistant pathogens, in particular
peptides to self-assemble into supramolecular structures, pro- the growth of antibiotic resistant bacteria strains.24
moted not only by the hydrophobic effect of long aliphatic Understanding the resistance mechanisms25 is key to tackling
chains, but also by establishing a hydrogen bonding network this problem from different perspectives, including health
through the backbone sequence of amino acids.
education,26 optimization27 and repurposing28 of current
The morphology of the self-assembling lipopeptides was drugs, development of new antibiotics29 or incorporating
studied using High Resolution Transmission Electron advanced genomic techniques.30 Lipopeptides have emerged
Microscopy (HR-TEM) and Field Emission Scanning Electron as a good strategy to develop new antibacterial agents;31 most
Microscopy (FE-SEM). While HR-TEM shows spherical and of the examples reported, so far, incorporated cationic amino
worm-like micelles between 20 and 100 nm for lipoamino acids, such as lysine or arginine.32 Mechanistic studies point
acids (Fig. 4A–C and Fig. S12 in the ESI†), multilamellar vesi- towards bacterial membrane disruption;33 however, alteration
cles of variable sizes, micelle clusters and fibers are observed of the membrane electric potential is also invoked.34
for lipodipeptides (Fig. 4D, E and Fig. S13, S14 in the ESI†).
FE-SEM revealed the formation of fibers of different lengths
for simple lipoamino acids, 1a–j, in most cases (Fig. 4F and G),
although amorphous aggregates have also been observed (see
the ESI†). Interestingly, diacylated cysteine, 1k, shows a more
complex pattern (Fig. 4H), while beautiful cross-linked fibers
and flower-like structures are observed for lipodipeptides
(Fig. 4I and J). Moreover, when fibers are detected, it is poss-
ible to visualize that they are formed by small spherical par-
ticles with an average diameter that ranges from 20 to 50 nm.
Fig. 5 Schematic self-assembly of lipopeptides.
These small spherical nanoparticles match the micellar struc-
Fig. 4 Representative HR-TEM and FE-SEM images of: 1a (A and F), 1f (B and G), 1k (C and H), 2d (D and I) and 3f (E and J).
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The antimicrobial activity of these new lipopeptides was logous N-fatty acyl derivatives 2. Remarkably, fatty amides 3
evaluated in vitro against Gram-negative (E. coli CECT 516) and show MIC values comparable to, or even lower than, highly cat-
Gram-positive (S. aureus CECT 240) strains. The Minimal ionic and structurally more complex lipopeptides previously
Inhibitory Concentration (MIC) was determined following the reported.32 Previous antimicrobial lipopeptides containing
broth microdilution method (see the ESI†). While all lipoa- both serine and histidine residues are embedded within a
mino acids bearing a single fatty acyl chain, 1a–j, are not active polycationic chain of several arginine or lysine residues.35
at a realistic concentration (up to 1000 μg mL−1), diacylated Alternatively, histidine gemini-lipopeptides with
a highly
cysteine 1k shows a notable activity and selectivity against complex pattern of substitution have been reported.36
S. aureus (Table 2). For dipeptide derivatives, we first screened
(4) No straightforward correlation has been found between
non-lipidated Ser-His and His-Ser dipeptides, which proved the CAC of these lipopeptides and their activity, suggesting
inactive against both strains, a control experiment that demon- that the antimicrobial mechanism might not be related to the
strates the importance of the amphiphilic nature, that allows detergent effect, but rather to the membrane and electro-
self-assembling, key to achieving antimicrobial activity (ESI†). chemical disruption quenching the cell viability. This is in
Considering N-terminus fatty acyl derivatives (2a–d), both agreement with the higher activity displayed by polycationic
N-decanoyl Ser-His (2a) and His-Ser (2c) showed modest and peptides and their increased ability to disrupt the bacterial
similar inhibitory activities against both strains (250–500 μg membrane.32,33 Moreover, elucidating whether these lipopep-
mL−1). However, N-oleyl derivatives (2b and 2d) were inactive. tides are bacteriostatic or bactericidal agents will need further
Finally, C-terminus fatty amides lead to interesting results, investigation.
where all examples bearing a single hydrophobic chain (3a–b
and 3d–e) are active against the two bacterial strains. From
this, oleyl derivatives (3b and 3e) are exceptionally active (40 μg
Conclusions
mL−1). Unfortunately, double hydrophobic chain derivatives,
In conclusion, we have synthesized a library of amphiphilic
short lipopeptides that combine N-fatty acyl amino acids and
all possible combinations of N- and C-lipidated dipeptides
from Ser and His. Their supramolecular behaviour has been
systematically studied, and their Critical Aggregation
Concentration (CAC), particle size, stability (zeta-potential)
3c and 3f, proved to be inactive.
From this, we can draw the following conclusions:
(1) Diacylated cysteine 1k is an outstanding example, as the
only active lipoamino acid, and the only example in the library
with such an impressive selectivity towards S. aureus. As far as
we are aware, there is no precedent for such a simple and
and morphology have been reported. In addition, their anti-
short lipoamino acid with this level of activity and selectivity.
microbial activity has been evaluated, showing promising
Shedding light on the mechanism of action of this diacylated
cysteine is part of our current efforts.
(2) For dipeptides, the most active ones (2a, 2c, 3b and 3e)
correlate with the smallest values of particle size (up to 10 nm
results with a respectable selectivity towards Gram-positive
strains for some examples. This study shows the importance of
new structurally simple and short lipopeptides as a tool to
develop novel, potent and selective antimicrobial agents,
size by number). However, we are aware that the Hydrophilic–
Lipophilic Balance (HLB) might also play an important role.21
where the self-assembling nature is indispensable for their
bioactivity.
(3) C-terminus fatty amides 3, bearing the N-terminal
ammonium group, are significantly more active than their ana-
Author contributions
Table 2 Antimicrobial activity results using lipopeptides
C.V.G. performed the experiments. C.V.G. and I.C. contributed
to designing and analysing the experiments, and writing, dis-
cussing and editing the manuscript. I.C. conceived and guided
the research.
MICa (μg mL−1
)
MICa (μg mL−1
)
E. coli
S. aureus
CECT
240
E. coli
S. aureus
CECT
240
CECT
CECT
Compound 516
Compound 516
1a
1b
1c
1d
1e
1f
1g
1h
1i
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
1000
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
250
>1000
500
>1000
500
40
>1000
250
40
250
>1000
500
>1000
125
40
>1000
250
40
Conflicts of interest
There are no conflicts to declare.
1000
>1000
>1000
>1000
>1000
>1000
>1000
40
Acknowledgements
This project received funding from the La Caixa Foundation
under the Junior Leader Program (No. LCF/BQ/PI19/11690020,
ID 100010434), CAM-Atracción de Talento (2019-T1/IND-12683)
and Spanish MICINN (PID2019-106327GA-I00). I. C. holds a
1j
1k
>1000
>1000
Gentamicin 4.037a
1.5637b
a Minimum concentration that inhibits proliferation after overnight
incubation.
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Ramón y Cajal fellowship from Spanish MICINN (RyC2019-
026674-I). We also thank Prof. Isabel Rodriguez
M. Olvera De La Cruz and M. J. Bedzyk, J. Phys. Chem. B,
2017, 121, 1623–1628.
(IMDEA-Nanociencia) for providing bacterial strains and 13 For a seminal outstanding contribution: J. D. Hartgerink,
Dr Jose Miguel González (ICB-CSIC) for helping with the
microscopy analysis.
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