Synthetic Ellagic Acid Glycosides Inhibit Early Stage Adhesion of Streptococcus agalactiae Biofilms as Observed by Scanning Electron Microscopy

Article abstract of DOI:10.1002/chem.202000354

Ellagic acid derivatives possess antimicrobial and antibiofilm properties across a wide-range of microbial pathogens. Due to their poor solubility and ambident reactivity it is challenging to synthesize, purify, and characterize the activity of ellagic acid glycosides. In this study, we have synthesized three ellagic acid glycoconjugates and evaluated their antimicrobial and antibiofilm activity in Streptococcus agalactiae (Group B Streptococcus, GBS). Their significant impacts on biofilm formation were examined via SEM to reveal early-stage inhibition of cellular adhesion. Additionally, the synthetic glycosides were evaluated against five of the six ESKAPE pathogens and two fungal pathogens. These studies reveal that the ellagic acid glycosides possess inhibitory effects on the growth of gram-negative pathogens.

Full text of DOI:10.1002/chem.202000354

A Journal of
Accepted Article
Title: Synthetic Ellagic Acid Glycosides Inhibit Early-Stage Adhesion
of Streptococcus agalactiae Biofilms as Observed by Scanning
Electron Microscopy
Authors: Schuyler A. Chambers, Jennifer Gaddy, and Steven
Townsend
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To be cited as: Chem. Eur. J. 10.1002/chem.202000354
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10.1002/chem.202000354
Chemistry - A European Journal
FULL PAPER
Synthetic Ellagic Acid Glycosides Inhibit Early-Stage Adhesion of
Streptococcus agalactiae Biofilms as Observed by Scanning
Electron Microscopy
Schuyler A. Chambers[a], Jennifer A. Gaddy[b]*, and Steven D. Townsend[a]*
Abstract: Ellagic acid derivatives possess antimicrobial and
antibiofilm properties across a wide-range of bacterial pathogens.
Due to their poor solubility and ambident reactivity it is challenging
to synthesize, purify, and characterize the activity of ellagic acid
glycosides. In this study, we have synthesized three ellagic acid
glycoconjugates and evaluated their antimicrobial and antibiofilm
activity in Streptococcus agalactiae (Group B Streptococcus, GBS).
Their significant impacts on biofilm formation were examined via
scanning electron microscopy (SEM) to reveal early-stage
inhibition of cellular adhesion. Additionally, the synthetic
glycosides were evaluated against five of the six ESKAPE
pathogens and two fungal pathogens. These studies reveal that
the ellagic acid glycosides possess inhibitory effects on the growth
of Gram-negative pathogens.
It was in this setting that we took an interest in the
ellagitannin class of natural products. These are a class of
hydrolysable tannins naturally occurring in a large number of
fruits, nuts, and vegetables (Figure 1).[5] These natural
products feature galloyl and glucoside units that are
subsequently oxidized and coupled in various ways to form
monomeric, dimeric, and higher-order oligomeric ellagitannins.
HO
OH
OH
OH
OH
OH
OH
O
HO
HO
OH
O
HO
O
O
O
OH
OH
O
O
O
O
O
HO
HO
O
O
O
O
HO
HO
O
O
O
(S)
O
OH
HO
OH
(S)
OH
HO
HO
OH
OH
Introduction
sanguiin H-5
OH
Nosocomial infections are the eighth leading cause of
death in the United States as ca. 10% of hospitalized patients
will acquire an infection from an opportunistic pathogen.[1] As a
key tool in their virulence, these microbes exist primarily in the
biofilm state which confers resistance to antimicrobial
chemotherapy.[2] Biofilm assembly occurs after planktonic
bacteria irreversibly attach to a surface, at which point they
produce an exopolysaccharide (EPS) matrix that encases and
protects their developing community. Biofilm mediated
infections feature increased resistance to antimicrobial agents,
often requiring therapeutic doses several orders of magnitude
higher than those needed to eradicate planktonic cells. The
inability of antibiotics to eradicate biofilms is attributed to a
number of factors.[3] First, the EPS matrix perturbs the diffusion
of chemotherapy throughout the biofilm community.
Additionally, cells in the biofilm state have slower metabolism,
reducing antibiotic efficacy. Finally, bacteria in the biofilm state
feature enhanced horizontal gene transcription. Driven by the
fact that bacteria in the biofilm state are up to 1000-fold more
resistant to antibiotics than their planktonic counterparts, the
development of new antibacterial agents that are also capable
of eradicating biofilms is of increased necessity.[4]
HO
pterocaryarin C
OH
OH
OH
HO
HO
O
HO
HO
HO
O
O
(S)
HO
O
O
O
O
O
O
OH
O
O
OH
O
O
HO
HO
HO
O
O
O
HO
O
HO
O
(R)
OH
HO
(S)
OH
HO
HO
OH
OH
HO
OH
pariin M
O
pedunculagin
O
O
O
OH
OH
RO
HO
OH
HO
OH
HO
HO
OH
glucoside
galloyl
hexahydroxydiphenoyl
(HHDP)
Figure 1: Select monomeric ellagitannins and common structural motifs.[6]
Of particular interest to our team was ellagic acid (EA, 1,
Figure 2) which is commonly isolated upon hydrolysis of
hexahydroxydiphenoyl (HHDP) containing ellagitannins. EA
exists primarily in its free acid oxidation state, in conjugation to
carbohydrates, or in more complex oligomeric forms as
represented by the ellagitannins.[7] EA and its conjugates have
historically served as important sources of pharmacologically
active compounds with cytotoxic, anti-oxidant, anti-
inflammatory, and anti-carcinogenic activity.[5] Indeed, elegant
studies recently published by Weinert and coworkers have
revealed that several glycosides of EA feature interesting
activity against methicillin-sensitive Staphylococcus aureus
(MSSA).[8] Their efforts focused on the synthesis of
glycosylated EA derivatives and used a unique TBAF-
mediated glycosylation to create two glycoconjugates of EA.[9]
The biological assays identified a rhamnosyl EA derivative that
had potent antibiofilm properties against a strain of MSSA with
[a]
Schuyler A. Chambers and Steven D. Townsend
Department of Chemistry
Vanderbilt University
7330 Stevenson Center, Nashville, Tennessee 37235, United
States
E-mail: steven.d.townsend@vanderbilt.edu
Jennifer A. Gaddy
[b]
Department of Medicine
Vanderbilt University Medical Center
1161 21st Ave South, D-3100 Medical Center North, Nashville,
Tennessee 37232, United States
E-mail: Jennifer.a.gaddy@vanderbilt.edu
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/chem.202000354
Chemistry - A European Journal
FULL PAPER
a 50% minimum biofilm inhibitory concentration (MBIC50) of 64
µg/mL. Their work held promise for the activity of these
glycoconjugates, but left room to further explore synthetic
optimization and diversity of biological activity. Of particular
interest is that the mechanism of action of ellagic acid
glycosides remains largely unknown. It has been postulated
that ellagitannins inhibit the growth of microorganisms by
sequestering metal ions critical for microbial growth, but direct
bacterial targets remain unidentified. Moreover, it is unclear
how these compounds modulate biofilm formation.[10]
In our initial foray, per-O-benzylation of methyl gallate
occurred in 85% yield and was followed by electrophilic
aromatic bromination using NBS to provide an intermediate
aryl bromide in 80% yield. Ullmann coupling of the aryl bromide
occurred in the presence of excess copper at elevated
temperature to provide biaryl 6 in moderate yield (Scheme 1).
This sterically-encumbered biaryl C-C bond is formed in
comparable yields to those of similar methyl ester substituted
systems.[12] Debenzylation and subsequent bislactonization
gave EA, which has extremely poor solubility in most organic
solvents.[13] As a result, EA was per-O-silylated, to arrive at 7
in 55-70% yield over three steps. Critically important, this
compound is soluble in organic solvents conventional for
glycosylation chemistry. To generate the EA glycosyl acceptor,
TBAF-mediated desymmetrization gave the C-3 phenol 8 in
85-90% yield.[11a] This has been previously confirmed to occur
at the C-3 position selectively, likely due to inductive effects of
the endocyclic lactone.
O
O
5
OH
OH
OH
OH
6
7
O
2’
4
3
O
O
HO
HO
HO
HO
O
1’
6’
1
2
3’
4’
OH
O
O
7’
HO
5’
O
O
ellagic acid (EA)
1
3-b-xyl-EA
2
O
O
O
HO
OH
OH
OH
HO
O
OBn
O
OH
OH
OBn
O
O
OH
1. BnBr, KI, K2CO3,
acetone, reflux, 85%
OH
O
HO
OH
O
O
MeO2C
BnO
OBn
HO
HO
O
HO
O
CO2Me
2. NBS, DMF, 80%
OH
3. Cu, DMF,100 ºC
30-60%
3-⍺-ara-EA
3-⍺-rha-EA
CO2Me
BnO
3
4
5
6
Figure 2: Structure of ellagic acid and synthetic ellagic acid glycosides.
OBn
The synthesis of EA glycoconjugates is complicated by
two challenges. First, EA and its derivatives are poorly soluble
in organic solvents. Secondly, any synthesis must proceed
through a phenolic O-glycosylation. Accordingly, the dual
prospects of thought-provoking chemistry and the opportunity
to evaluate new agents of potential value to circumventing
antibiotic resistance served to identify glycosides of EA as an
appropriate target for a total synthesis program.
4. Pd(OH)2, H2, EtOAc
5. MeOH, H2O, reflux
6. TIPSCl, DMAP
DMF, 80 ºC
55-70%, 3 steps
OTIPS
OTIPS
OTIPS
OH
O
O
O
O
7. TBAF, CH2Cl2
85-90%
Results and Discussion
O
O
O
O
At the planning stage we sought to develop a platform to
access EA glycosides incorporating different monosaccharide
residues. Our goal was to identify which monosaccharide
conferred the most potent antimicrobial activity. Structurally,
we set out to synthesize EA glycosides featuring xylose,
arabinose, and rhamnose monosaccharides (Figure 2). To
TIPSO
TIPSO
8
7
OTIPS
OTIPS
Scheme 1: Synthesis of ellagic acid glycosyl acceptor.
Glycosylation studies began with ⍺ and β per-O-
acetylated and per-O-benzylated trichloroacetimidate xylosyl
donors activated with TMSOTf or BF3∙OEt2. These reactions
were unproductive at temperatures ranging from -78oC to
23oC.[14] In every case, we observed donor hydrolysis and
recovery of 8. Given the difficulties associated with forming
aromatic glycosides, we evaluated glycosyl halide donors
under both Koenigs-Knorr (i.e. halophilic promoters such as
Ag2CO3) and basic conditions.[15] Unfortunately, the reaction
proved obstinate and the glycosidic bond remained unformed.
To access the glycosides, we applied Weinert’s in situ TBAF
deprotection / glycosylation strategy.[8b] Under these conditions,
7 is desymmetrized by removing the silyl ether at C-3 to
produce an intermediate quaternary ammonium salt. Next, the
salt is reacted under Gervay-Hague conditions with a glycosyl
iodide donor and TBAI at elevated temperature.[15] The
reaction proceeded for 48 hours to produce the desired
glycosides 9-11, albeit in 15-30% yield (Scheme 2).[9, 16]
date, a number of syntheses have been reported for glycosides
11]
of EA.[8b,
Herein, we describe our synthetic approach
centering around a copper mediated Ullmann coupling and a
phenolic O-glycosylation (Figure 3A). In theory, the route can
provide access to novel derivatives of EA featuring unnatural
aryl substitution; derivatives that are otherwise inaccessible
when starting from commercially available EA (Figure 3B).
A. Synthetic Approach
B. Synthetic Ellagic Acid Derivatives
O
O
RO
O
O
O
OR
OR
O
O
O
RO
RO
Glycosylation
O
O
O
Ullman
O
Coupling
Figure 3: Ellagic acid glycosides. A. Synthetic approach B. Highlighted
positions of possible derivatization via route to ellagic acid.
2
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10.1002/chem.202000354
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FULL PAPER
O
OTIPS
OTIPS
OR
O
OH
OTIPS
O
OH
O
O
O
i. K CO , DMF/H O
8. i. TBAF, CH2Cl2
9.
2
3
2
O
O
O
O
O
O
ii. TBAI, Iodide
35 ºC, 15-30%
ii. K2CO3, MeOH/H2O
40-60%
O
O
O
9: b-D-xyl(Ac)3
10: ⍺-L-ara(Ac)3
11: ⍺-L-rha(Ac)3
O
7
TIPSO
TIPSO
HO
OTIPS
OTIPS
OH
O
O
Products
O
Glycosyl Iodide Donors
OH
HO
OH
OH
O
OAc
O
O
O
O
AcO
O
OH
OH
O
O
HO
HO
O
AcO
AcO
AcO
HO
OH
O
OH
OH
OH
I
O
O
AcO
O
O
I
HO
HO
HO
I
O
O
HO
O
OH
O
3-⍺-rha-EA
3-⍺-ara-EA
3-
β
-xyl-EA
2
AcO
AcO
4
3
OAc
Scheme 2: Completed synthesis of ellagic acid glycosides.
Table 1: Minimum inhibitory concentration (MIC) and minimum biofilm
While these reactions are reproducible, their low yields
are attributed to the poor nucleophilicity of EA and unforeseen
removal of additional TIPS protecting groups. This unwanted
removal of protecting groups impacted the solubility of the
substrate and prevented further reaction. Lastly, the reaction
produces the 1,2-trans-glycoside selectively.[8b] Glycosides 9-
11 were subjected to a one-pot, two-step global deprotection
strategy (silyl ether cleavage and ester saponification) to
provide EA glycosides 2-4.
Based on their reported effects against the Gram-positive
pathogen S. aureus, we hypothesized EA glycosides would
possess antimicrobial and antibiofilm activity in our lab’s model
Gram-positive pathogen, Streptococcus agalactaie (Group B
Streptococcus, GBS). We assayed against two clinical strains
of GBS; GB590 (serotype Ia) and GB2 (serotype III).[17] These
two serotypes represent the most prevalent serotype classes
isolated from clinical infections in the United States.[18] The
minimum inhibitory concentration (MIC) and minimum biofilm
inhibitory concentration (MBIC) results are summarized in
Table 1. The synthetic EA glycosides 2-4 possessed modest
antimicrobial activity against GBS. The EA arabinoside 3 was
the most potent, with an MIC90 of 1024 µg/mL in both strains.
More interestingly, glycosides 2 and 3 possessed antibiofilm
properties at sub-inhibitory concentrations of 512 µg/mL in
both GBS strains. It should be noted that we attempted to used
EA as a control compound, but due to its low solubility, could
only reach a maximum dose of 256 µg/mL. No changes to
bacterial growth or biofilm formation were seen at this highest
concentration.
inhibition concentration (MBIC) in GBS strains[a,b]
GB2
Compound
MIC50
ND[c]
1024
1024
MIC90
ND[c]
MBIC50
512
MBIC90
1024
2
3
4
1024
ND[c]
512
1024
1024
ND[c]
GB590
MIC90
ND[c]
Compound
MIC50
1024
1024
1024
MBIC50
1024
512
MBIC90
1024
2
3
4
1024
1024
1024
1024
1024
[a] all values reported in µg/mL; [b] data representative of three biological
replicates, each with three technical replicates; [c] ND – not determined;
>1024
We further analyzed changes to biofilm production as a
measure of the ratio of biofilm to biomass (biofilm/biomass,
OD560/OD600).[19] This parameter enables verification of
whether or not a phenotypic change in biofilm is due to lower
cellular growth or inherent stunting of biofilm production. The
results in Figure 4 demonstrate changes to biofilm to biomass
ratios within both GBS strains upon treatment with EA
glycosides 2-4. In both strains, 2 and 3 show significant effects
on biofilm/biomass, while 4 shows little to no effect. This
demonstrates that 2 and 3 are impacting biofilm adhesion and
formation itself, rather than just affecting the presence of
planktonic cells.
Since 4 does not exhibit the same trend in activity, there
is carbohydrate specificity to the anti-biofilm activity.
Furthermore, this carbohydrate specificity is not conserved
across Gram-positive species, as 4 had been previously
shown to be potent in MSSA systems.[8b] Additionally, while
higher concentrations of the EA glycosides result in diminished
biofilm formation, lower concentrations can actually promote
growth of GBS biofilms, illustrating that the effects are
concentration dependent.
3
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10.1002/chem.202000354
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Figure 4: Biofilm production as denoted by the ratio of biofilm/biomass (OD560/OD600) in GB590 and GB2 in the presence glycosylated EA derivatives relative to
biofilm production in Todd-Hewitt broth (THB) alone. Data displayed represent the relative mean biofilm/biomass ratio ± SEM of at least three independent
experiments, each with three technical replicates. * represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, and **** represents p < 0.0001 by one-
way ANOVA, comparing biofilm production of GBS in each EA glycoside supplementation condition to biofilm production of GBS in media alone (Untreated).
Figure 5: Scanning electron micrographs of GB590 biofilm formation in Todd-Hewitt broth (THB) after 24 h. A. GBS590 at 20,000x magnification B. GBS590
when treated with 512 µg/mL of 3 at 20,000x magnification. C. GBS590 at 50,000x magnification. D. GBS590 when treated with 512 µg/mL of 3 at 50,000x
magnification.
4
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As the mechanism of action for these compounds
remains largely unknown, we moved forward with
characterizing their anti-biofilm properties using scanning
electron microscopy (SEM) images of the GBS biofilm. Our
goal was to visualize what structural perturbations might have
occurred as a result of treatment with the synthetic glycosides.
As arabinosyl glycoside 3 had not been previously synthesized,
we chose to image its effects on biofilm formation within GB590
when dosed at 512 µg/mL. The images in Figure 5 are
representative of the displayed phenotype upon treatment with
3. In the untreated control samples, while there is not much
EPS yet formed, the GBS cells have adhered globally in a
monolayer fashion. The cellular coverage is universal across
the slide and cells are starting to stack vertically on one another,
as demonstrated in the low magnification (Figure 5A). Higher
magnification demonstrates the bacterial contacts involved in
cellular stacking and clearly shows the presences of cell-
adhesion molecules (CAMs) likely involved in initial cell
adhesion processes (Figure 5C). This is indicative of good
initial adherence to the surface, from which heartier biofilm
structure can form over longer incubation times.
Alternatively, in the samples treated with 3, there is a lack
of universal coverage or monolayer cellular adhesion. At low
magnification we see sparse adherence of cells and few
occurrences of three-dimensional architecture or cellular
stacking (Figure 5B and 5D). There appears to be some
extracellular matrix, likely carbohydrate in nature, but it does
not seem to be aiding in global cellular adhesion. Since there
is not uniformed coverage of cells, the biofilm cannot mature
into a complex architecture. As a result, we hypothesize that
the ellagic acid glycosides limit initial adhesion mechanisms in
GBS biofilm formation. This initial limitation stunts the ability of
GBS to grow dense architectures typically seen from robust
biofilm forming microbes. Such mechanisms of biofilm
inhibition are broadly applicable to the prevention of biofilm
formation on surfaces and medical devices, and offer
opportunities in fighting antibiotic-resistant infections.
methicillin-resistant Staphylococcus aureus (MRSA), ranging
from 42-50% growth inhibition across all of the glycosides
(Table 2). Interestingly, EA also significantly decreased growth
of MRSA by 65%, suggesting activity in this pathogen is not
carbohydrate dependent.
Additionally, the EA glycosides 2-4 showed broad
inhibition of growth within the Gram-negative pathogens, most
notably 43% inhibition in Acinetobacter baumanii for 2 and 45%
inhibition of Klebsiella pneumoniae when treated with 4. As
these pure compounds had not been previously tested for
antibacterial properties against Gram-negative pathogens,
these results suggest that EA glycosides may have broad
spectrum antibiotic properties. In these pathogens the EA
glycosides largely outperform free EA, indicating
a
carbohydrate-specific antibacterial effect. Finally, growth of the
fungus Candida albicans was not significantly impacted by any
of the derivatives, but the introduction of 2 significantly
promoted growth of Cryptococcus neoformans. Curiously, the
primary virulence factor of Cryptococcus neoformans is its
capsular polysaccharide, which features xylose in its repeating
unit.[21] We hypothesize that C. neoformans can use the xylose
residue from 2 to synthesize its capsular polysaccharide,
ultimately promoting cellular growth. This observation, in
addition to the antibacterial properties of these derivatives
within Gram-negative pathogens, has fueled ongoing
experiments to study biofilm perturbations in these pathogens.
Conclusion
In conclusion, we have developed a platform to synthesize EA
glycosides featuring a sterically encumbered Ullmann coupling
and phenolic O-glycosylation. The synthesis has been used to
generate three EA glycosides that have demonstrated
antibiofilm properties within multiple strains of Streptococcus
agalactiae. Visualization with scanning electron microscopy
has revealed that these glycosides stunt biofilm growth at the
early level of initial bacterial adhesion, preventing further
extracellular matrix from forming. The compounds also
illustrate broad-spectrum activity against the ESKAPE
pathogens, with their activity notably spanning into Gram-
negative pathogens. Future studies will focus on synthesizing
(i) C4 modified ellagic acid glycosides and (ii) modified ellagic
acid arabinosides. We will probe their structure function
relationships using the platform developed herein. Results in
this regard will be reported in due course.
With ample understanding of the antimicrobial properties
of EA glycosides in Gram-positive models, we wanted to
investigate their broad-spectrum antimicrobial activity in model
Gram-negative organisms. Accordingly, we leveraged the
Community for Open Antimicrobial Drug Discovery (COADD)
at the University of Queensland, that offers free antibacterial
activity screening against five of the ESKAPE pathogens, in
addition to Cryptococcus neoformans and Candida albicans.[20]
EA and the three synthetic EA glycosides 2-4 were analyzed
in bacterial growth inhibition assays dosed at a constant
concentration of 32 µg/mL. All glycosides showed broad
antibacterial activity in both the Gram-positive and Gram-
negative microbes. The highest rates of activity were seen in
Table 2: Growth inhibition of EA glycosides against additional pathogens[a,b]
Compound
S. aureus
E. coli
K. pneumoniae
P. aeruginosa
A. baumannii
C. albicans
C. neoformans
2
3
50
42
42
65
44
25
38
5
39
26
45
11
8
23
18
3
43
25
35
8
12
14
25
21
-86[c]
-6[c]
-2[c]
3
4
EA
[a] Assay conditions performed according to CO-ADD Standard Operating Procedures[20]
[b] All values expressed in percent growth inhibition (%)
[c] Negative number is attributed to growth of C. neoformans
5
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10.1002/chem.202000354
Chemistry - A European Journal
FULL PAPER
Acknowledgements
[15]
[16]
[17]
K. J. Jensen, M. Meldal, K. Bock, J Chem Soc, Perk
Trans 1 1993, 2119-2129.
This work was supported by the National Institutes of Health
under Grants No. 1R35GM133602 to S.D.T and
5R01HD090061 to J.A.G. S.A.C. was supported by the
Vanderbilt Chemical Biology Interface (CBI) training program
(T32 GM065086). Dr. Shannon Manning of Michigan State
University is acknowledged for providing clinical strains of GBS
(GBS 00590 and GBS 00002). The antimicrobial screening
performed by CO-ADD (The Community for Antimicrobial Drug
Discovery) was funded by the Wellcome Trust (UK) and The
University of Queensland (Australia). We thank the Vanderbilt
Small Molecule NMR Core for collection of structural data, in
addition to the CISR Core for aid in SEM sample preparation.
B. Mukhopadhyay, K. P. R. Kartha, D. A. Russell, R. A.
Field, J Org Chem 2004, 69, 7758-7760.
aH. D. Davies, C. Adair, A. McGeer, D. Ma, S.
Robertson, M. Mucenski, L. Kowalsky, G. Tyrell,
Carol J. Baker, J Infect Dis 2001, 184, 285-291; bS. D.
Manning, M. A. Lewis, A. C. Springman, E. Lehotzky,
T. S. Whittam, D. Davies, Clin Infect Dis 2008, 46,
1829-1837.
P. Melin, A. Efstratiou, Vaccine 2013, 31, D31-D42.
aD. L. Ackerman, K. M. Craft, R. S. Doster, J. H.
Weitkamp, D. M. Aronoff, J. A. Gaddy, S. D.
Townsend, ACS Infect Dis 2018, 4, 315-324; bD. L.
Ackerman, R. S. Doster, J. H. Weitkamp, D. M. Aronoff,
J. A. Gaddy, S. D. Townsend, ACS Infect Dis 2017, 3,
595-605;
[18]
[19]
[20]
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M. A. T. Blaskovich, J. Zuegg, A. G. Elliott, M. A.
Cooper, ACS Infect Dis 2015, 1, 285-287.
D. Srikanta, F. H. Santiago-Tirado, T. L. Doering, Yeast
2014, 31, 47-60.
Keywords: ellagic acid glycosides • antibiofilm activity •
Streptococcus agalactiae • scanning electron microscopy •
ESKAPE pathogens
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This article is protected by copyright. All rights reserved.

10.1002/chem.202000354
Chemistry - A European Journal
FULL PAPER
Synthetic ellagic acid glycosides possess carbohydrate-
specific antibiofilm effects against Streptococcus agalactiae.
Scanning electron microscopy has revealed that these
compounds likely inhibit early-stage bacterial adhesion
mechanisms. These compounds additionally possess
antimicrobial activity against gram-negative ESKAPE
pathogens, further broadening the antibiotic profile of synthetic
ellagic acid glycosides.
Institute and/or researcher Twitter usernames:
@Townsend_Lab @VanderbiltChem
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This article is protected by copyright. All rights reserved.