Discovery of quinoline small molecules with potent dispersal activity against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis biofilms using a scaffold hopping strategy

Article abstract of DOI:10.1016/j.bmcl.2014.09.009

Staphylococcus aureus and Staphylococcus epidermidis are recognized as the most frequent cause of biofilm-associated nosocomial and indwelling medical device infections. Biofilm-associated infections are known to be highly resistant to our current arsenal of clinically used antibiotics and antibacterial agents. To exacerbate this problem, no therapeutic option exists that targets biofilm-dependent machinery critical to Staphylococcal biofilm formation and maintenance. Here, we describe the discovery of a series of quinoline small molecules that demonstrate potent biofilm dispersal activity against methicillin-resistant S. aureus and S. epidermidis using a scaffold hopping strategy. This interesting class of quinolines also has select synthetic analogues that demonstrate potent antibacterial activity and biofilm inhibition against S. aureus and S. epidermidis.

Full text of DOI:10.1016/j.bmcl.2014.09.009

Accepted Manuscript
Discovery of quinoline small molecules with potent dispersal activity against
methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis
biofilms using a scaffold hopping strategy
Yasmeen Abouelhassan, Aaron T. Garrison, Gena M. Burch, Wilson Wong,
Verrill M. Norwood IV, Robert W. Huigens III
PII:
S0960-894X(14)00934-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.09.009
BMCL 21975
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 August 2014
30 August 2014
2 September 2014
Please cite this article as: Abouelhassan, Y., Garrison, A.T., Burch, G.M., Wong, W., Norwood, V.M. IV, Huigens,
R.W. III, Discovery of quinoline small molecules with potent dispersal activity against methicillin-resistant
Staphylococcus aureus and Staphylococcus epidermidis biofilms using a scaffold hopping strategy, Bioorganic &
Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.09.009
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Discovery of quinoline small molecules with
potent dispersal activity against methicillin-
resistant Staphylococcus aureus and
Staphylococcus epidermidis biofilms using a
scaffold hopping strategy
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Yasmeen Abouelhassan, Aaron T. Garrison, Gena M. Burch, Wilson Wong, Verrill M. Norwood IV, and Robert
W. Huigens III

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Discovery of quinoline small molecules with potent dispersal activity against
methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis
biofilms using a scaffold hopping strategy
Yasmeen Abouelhassan, Aaron T. Garrison, Gena M. Burch, Wilson Wong, Verrill M. Norwood IV, and
Robert W. Huigens III*
University of Florida, Department of Medicinal Chemistry, College of Pharmacy, 1600 SW Archer Rd., Gainesville, FL 32610, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Staphylococcus aureus and Staphylococcus epidermidis are recognized as the most frequent
cause of biofilm-associated nosocomial and indwelling medical device infections. Biofilm-
associated infections are known to be highly resistant to our current arsenal of clinically used
antibiotics and antibacterial agents. To exacerbate this problem, no therapeutic option exists that
targets biofilm-dependent machinery critical to Staphylococcal biofilm formation and
maintenance. Here, we describe the discovery of a series of quinoline small molecules that
demonstrate potent biofilm dispersal activity against methicillin-resistant S. aureus and S.
epidermidis using a scaffold hopping strategy. This interesting class of quinolines also has
select synthetic analogues that demonstrate potent antibacterial activity and biofilm inhibition
against S. aureus and S. epidermidis.
Revised
Accepted
Available online
Keywords:
Drug Discovery;
Biofilm Dispersal Agent;
Biofilm Inhibitor;
Antibacterial Agent;
Quinoline
2009 Elsevier Ltd. All rights reserved.
Bacterial
biofilms
are
surface-attached
bacterial
chemotypes or scaffolds exist that target Staphylococcal
communities that form when free-floating (planktonic) bacteria biofilms.10,11
use endogenous signaling molecules in a process called quorum
sensing to coordinate the simultaneous attachment to a
surface.1-4 Biofilms are notorious for their resistance to
conventional antibiotics, microbicidal agents and host immune
responses.1,2 These bacterial communities are highly prevalent
in medicine as bacterial biofilms are associated with ~80% of
all bacterial infections.2,5 To make matters worse, we currently
have no approved therapeutic treatment options that target
machinery critical to biofilm formation or biofilm maintenance.
Figure 1. Scaffold hopping strategy to discover novel antibacterial
and antibiofilm small molecules.
Staphylococci are frequently encountered by humans as
commensal bacteria found on skin and mucous surfaces, which
contributes significantly to their status of being involved in
more biofilm-associated infections than other pathogens.6
Drug-resistant S. aureus and S. epidermidis infections are a
major clinical problem in biofilm-related diseases, such as:
osteomyelitis, indwelling medical device infection (in
particular, central venous catheter S. epidermidis infections),
chronic wound infection, endocarditis, periodontitis, peri-
implantitis, mixed biofilm infections and ocular infection.6-9
Despite the alarming need, very few small molecule
Our group recently discovered that bromophenazine
1
possesses potent antibacterial activity against S. aureus and S.
epidermidis (MICs between 0.78-1.56 µM or 0.28-0.55
µg/mL).12 Using a scaffold hopping approach13,14 (Figure 1),
we were curious to know how halogenated quinolines
structurally similar to 1, such as broxyquinoline 2, would
perform in antibacterial and antibiofilm assays against S.
aureus and S. epidermidis as a major goal for our group is to
identify novel antibacterial and/or antibiofilm compounds.

Figure 2. Structures of the quinolines evaluated against Staphylococcal pathogens.
Using this scaffold hopping approach, we evaluated a focused pathogens, which included: S. aureus ATCC 29213, S.
library of 21 quinoline small molecules (Figure 2). We epidermidis ATCC 12228, A. baumannii ATCC 19606 and P.
initiated this study with the chemical synthesis of 16 quinolines
aeruginosa PAO1/BAA-47. This panel of pathogens included
using standard synthetic approaches to construct appropriate both gram-positive (S. aureus and S. epidermidis) and gram-
halogenated quinoline scaffolds or esters of halogenated 8- negative (A. baumannii and P. aeruginosa) bacteria to
hydroxyquinoline derivatives (Scheme 1). Five quinolines, determine the spectrum of activity of our quinolines. In
including broxyquinoline 2 and nitroxoline, were obtained addition to ATCC strains, we evaluated these quinolines against
commercially for these investigations. Nitroxoline is an several S. aureus clinical isolates, including several methicillin-
antibiotic used to treat urinary tract infections due to its
resistant S. aureus isolates and a S. epidermidis clinical isolate
bacteriostatic activity against Escherichia coli15,16 and (Supplementary Table 2; Supporting Information) from patients
antibiofilm activity against Pseudomonas aeruginosa.17 treated at UF Health Shands Hospital (Gainesville, FL).
Nitroxoline elicits these activities through the chelation of
various metals, including zinc.15-17
Interestingly, in head-to-head MIC experiments, quinoline 2
was 8- to 16-fold less potent than bromophenazine 1 against S.
aureus and S. epidermidis strains (Table 1.) despite being 4- to
8-fold more potent against A. baumannii (Supplementary Table
1; Supporting Information). Neither bromophenazine 1 nor
quinoline 2 displayed any detectable growth inhibition activity
against P. aeruginosa at the highest concentration tested (i.e.,
100 µM). Despite the reduction in antibacterial activity from 1
to 2, quinolines 4, 7 and 10 demonstrated a 2- to 4-fold increase
in potency in antibacterial activity (MIC 0.39-0.78 µM) against
S. aureus18 ATCC 29213 compared to bromophenazine 1 (MIC
1.56 µM). Quinolines 7 and 10 also demonstrated similar
potency increases in antibacterial activity against S. epidermidis
when compared to 1. In addition, we found quinolines 4, 7, 9
and 10 to demonstrate potent antibacterial activity (MIC values
between 0.2 and 1.56 µM) against a panel of six clinical
isolates of S. aureus (Supplementary Table 2; Supporting
Information).
We then evaluated our quinoline library in biofilm dispersion
assays against methicillin-resistant S. aureus clinical isolate
MRSA-2 and S. epidermidis ATCC 12228. The dispersion, or
clearance, of established S. aureus and S. epidermidis biofilms
has continued to remain a critical biomedical challenge and we
were curious to know if our library of quinolines was capable
of dispersing established Staphylococcal biofilms. We selected
MRSA-2 and S. epidermidis ATCC12228 as model strains for
this biofilm study due to their ability to form robust biofilms as
determined by crystal violet staining in 96-well polystyrene
plates.
Scheme 1. Rapid synthesis of (A) halogenated quinolines and (B)
ester derivatives using standard synthetic approaches.
With our library of 21 quinolines in hand, we first evaluated the
ability of these quinolines to inhibit bacterial growth in
microdilution MIC experiments head-to-head against
(positive control) using a panel of four clinically relevant
1

Table 1. Antibacterial and biofilm dispersion activities of select
quinolines against S. aureus and S. epidermidis.
results; however, quinolines 8 and 4 demonstrated outstanding
potency against established S. epidermidis biofilms with EC50
values of 3.26 µM and 5.56 µM, respectively (see Table 1). As
a library, 16 of the 21 (76%) quinolines were found to be
“active” dispersal agents and reported EC50 values of ≤30 µM.
From our biofilm dispersion studies, we found 13 of the 21
(62%) quinolines demonstrated “good” potency as biofilm
dispersal agents (EC50 values of ≤15 µM) while 4 of the 21
(19%) quinolines demonstrated “outstanding” potency as
dispersal agents against S. epidermidis biofilms (EC50 values of
≤10 µM; complete biofilm dispersion data in Supporting
Information).
S. aureus [a]
antibacterial
activity
S. aureus [b]
biofilm
dispersion
EC50 (µM)
S. epi.[c]
antibacterial
activity
S. epi. [c]
biofilm
dispersion
EC50 (µM)
Compound
MIC (µM)
MIC (µM)
2
12.5
12.5
9.49
14.9
2.60
6.55
13.6
2.55
2.09
2.06
2.74
3.30
10.5
12.5
12.5
14.0
>200
9.17
11.8
5.56*
12.8
3.26
>200
19.8
12.3
14.2
3
4
0.39
0.78-1.56
3.13
5
3.13-6.25
6.25
We also determined EC90 values for the biofilm dispersal
activity of our quinoline library against S. epidermidis
(Supplementary Table 4; Supporting Information). Quinoline 8
reported an EC90 value of 28.8 µM, which was the most potent
biofilm dispersal activity in our quinoline library. The large
majority of the biofilm dispersion active quinolines reported
EC90 values between 110 and 200 µM.
6
3.13
7
0.39-0.78
0.78-1.56
1.56
0.39-0.78
1.56
8
9
10
>100
0.39
0.39
11
6.25
3.13
nitroxoline
25
12.5-25
[a] S. aureus strain ATCC 29213 used for MIC. [b] S. aureus strain
MRSA-2 used for biofilm dispersion. [c] S. epidermidis strain ATCC
12228 used for MIC and biofilm dispersion. *EC50 value obtained for
a biofilm dispersal agent that demonstrates 51 1% biofilm dispersion
at 200 µM compared to DMSO controls. All other biofilm dispersal
agents were ≥80% effective in biofilm dispersion assays against S.
epidermidis ATCC 12228.
Several quinolines demonstrated potent biofilm dispersal
activity against MRSA-2 (Table 1 & Figure 3). Four quinoline
derivatives (i.e., quinolines 4, 7, 9, 10) demonstrated very
potent biofilm dispersion against MRSA-2 with EC50 values
<2.80 µM. Quinoline 9 (EC50 = 2.06 µM) demonstrated the
most potent biofilm dispersion activity during the course of our
investigations. As a collection, this focused library of 21
quinolines was highly effective in the dispersion, or clearance,
of established MRSA-2 biofilms. Results from our biofilm
dispersion experiments with MRSA-2 show that 17 of the 21
quinolines (81%) evaluated were found to be “active” biofilm
dispersal agents by reporting EC50 values of ≤15 µM. Further
analysis of our MRSA-2 biofilm dispersion results reveal that
14 of the 21 quinolines (67%) demonstrated “good” potency
with EC50 values ≤10 µM while 7 of the 21 quinolines (33%)
demonstrated “outstanding” biofilm dispersion potency with
EC50 values ≤5 µM (complete biofilm dispersion data in
Supporting Information).
Figure 3. Biofilm dispersion assays of potent biofilm dispersal agents
against: A.) MRSA-2 (quinolines 8 and 9) and B.) S. epidermidis
(quinolines 8 and 11). A dose-response curve is presented for
quinoline 9 against MRSA-2 biofilms.
With the goal of identifying promising quinolines capable of
completely clearing established MRSA biofilms, we
determined EC90 values for each of our quinolines
(Supplementary Table 3; Supporting Information). Quinolines
8 and 9 were found to be the most potent quinolines in our
library with EC90 values of 16.6 µM and 17.4 µM, respectively.
Six of the 21 quinolines in this study reported EC90 values <30
µM against established MRSA-2 biofilms.
In addition to biofilm dispersion, a second major goal of our
research program is to identify small molecule biofilm
inhibitors that operate via non-growth inhibiting mechanisms.
Biofilm inhibitors that operate via mechanisms independent of
growth inhibition mimic quorum sensing antagonists and place
little, if any, stress on bacteria to develop resistance. Although
we determined that our quinoline small molecules had
moderate to good antibacterial (i.e., growth inhibiting)
activities in our initial MIC experiments, we were curious to
In addition to S. aureus, we also evaluated our library of
quinolines against S. epidermidis ATCC 12228 in biofilm
dispersion assays (Table 1 & Figure 3). As a collection, these
quinoline small molecules were slightly less potent against S.
epidermidis compared to the MRSA-2 biofilm dispersion assay

see if any of our quinoline derivatives possessed biofilm antibiotic) suggests that these two quinoline small molecules
inhibition activity that was independent of growth inhibition possibly operate via alternative primary mechanisms.
against Staphylococcal strains.
TPEN is an established zinc-chelator which was used as a
Biofilm inhibition assay parameters were optimized for S. control in our investigations in Staphylococcal biofilm
aureus and S. epidermidis biofilm formation (i.e., glucose
supplementation, higher bacterial load and longer incubation reported to demonstrate planktonic toxicity against S. aureus.20
periods) which was necessary to achieve a dense and robust In our biofilm inhibition assays against S. aureus ATCC 29213,
Staphylococcal biofilm in microtiter plates. As a result of these TPEN reported an MIC:IC50 ratio of 1.8 which corresponds to
growth promoting conditions, a new set of MIC values for high antibacterial (growth inhibiting) phenotype being the
inhibition experiments (Table 2). TPEN has previously
“biofilm inhibition conditions” was generated for our quinoline primary mechanism for biofilm inhibition.
library (Table 2). MIC values in these biofilm inhibition assays
Table 2. Biofilm inhibition assay results for quinolines and antibiotic
controls against S. aureus (ATCC 29213).
were typically higher (up to >16-fold higher) than standard
MIC assay protocols across the quinoline library. The
advantage of using this approach to evaluate potential biofilm
inhibitors is that the evaluation of planktonic “toxicity” and
biofilm inhibition can be carried out using a single assay. We
compared the “biofilm inhibition” assay MIC values to the
biofilm inhibition activity (IC50 values obtained from crystal
violet staining of biofilms in 96-well plates) generated in these
biofilm inhibition assays and obtained a MIC:IC50 ratio to
characterize the biological activity of our quinolines as either
“biofilm inhibitors” or “antibacterial agents” (growth
inhibitors).
S. aureus [a]
antibacterial
activity
S. aureus [a]
biofilm
MIC:IC50
Ratio
Compound
Phenotype
inhibition
IC50 (µM)
MIC (µM)
2
25
>100
6.25
2.55
3.49
1.14
0.89
4.45
0.76
2.66
>100
1.03
1.06
6.50
34.8
0.30
0.51
9.8
>28.7
5.5
Antibacterial
Biofilm Inh.
Antibacterial
Antibacterial
Biofilm Inh.
Antibacterial
Antibacterial
Inactive
3
4
5
6.25
7.0
From our biofilm inhibition experiments, we determined that
quinolines 3 and 6 possess “biofilm inhibition” activity against
S. aureus (Table 2) and S. epidermidis (see Supplementary
Table 3; Supporting Information). Quinoline 3 is commercially
available; however, quinoline 6 is a novel small molecule that
was found to be essentially non-toxic to planktonic (MIC >100
µM) while inhibiting biofilm formation with good potency
(IC50 = 4.45 µM) by reporting an MIC:IC50 ratio of >22.5
against S. aureus ATCC 29213. Quinoline 6 demonstrated
antibacterial activity (MIC = 6.25 µM) under standard MIC
conditions, but it is clear from our biofilm inhibition assays that
6 possesses the ability to inhibit S. aureus biofilm formation at
concentrations that do not inhibit planktonic growth (Table 2;
Supporting Information for images of this experiment). Other
quinolines from this library were determined to have
antibacterial activity and reported MIC:IC50 ratios between 2.3
and 13.1 in head-to-head biofilm inhibition assays against S.
aureus (see Supporting Information for details on all quinoline
library members). MIC:IC50 ratios between 4 and >20 have
been previously reported for 2-aminobenzimidazole biofilm
inhibitors; however, that study reported MIC values and biofilm
inhibition activity using separate assay conditions.19
6
>100
6.25
>22.5
8.2
7
8
6.25-12.5
>100
6.25
7.0
9
--
10
6.1
Antibacterial
Antibacterial
Antibacterial
Antibacterial
Antibacterial
Antibacterial
11
6.25
5.9
nitroxoline
TPEN
erythro.
vanco.
25
3.8
62.5
1.8
1.56-3.13
1.56
7.8
3.1
[a] S. aureus strain ATCC 29213 was used to obtain MIC and IC50
values from same biofilm inhibition experiment (assay optimized for
biofilm formation). NOTE: Antibiotic abbreviations: erythro.=
erythromycin; vanco. = vancomycin.
It is interesting to note activity profile differences between
nitroxoline and several active brominated quinolines identified
during these investigations. Nitroxoline is known to have
bacteriostatic activity against E. coli and antibiofilm activity
against P. aeruginosa, which is why this agent is used to treat
reccurring urinary tract infections. In these studies, we found
nitroxoline to demonstrate good antibacterial activity against A.
baumannii (MIC 6.25 µM; Supplementary Table 1.) and only
moderate to weak antibacterial activity against S. aureus and S.
epidermidis (MICs 12.5-50 µM). Nitroxoline’s activity profile
does not highly correlate with the Staphylococcal active
bromoquinoline small molecules that were identified during the
course of these investigations. These differences could point to
alternative mechanisms as the primary mode-of-action for the
halogenated quinolines described here. Future investigations
will aim to interrogate mechanistic differences between
nitroxoline and the brominated quinoline small molecules;
however, a metal-chelating mechanism for these quinolines
cannot be eliminated with our current findings. Metal-chelating
In addition to our quinolines, we determined MIC:IC50 ratios
for two antibiotics (vancomycin and erythromycin) to serve as a
reference for “antibacterial activity” in head-to-head biofilm
inhibition experiments (Table 2). In our biofilm inhibition
experiments against S. aureus, vancomycin gave a MIC:IC50
ratio of 3.1 while erythromycin reported a MIC:IC50 ratio of
7.8. From this series of biofilm inhibition experiments against
S. aureus, we concluded that MIC:IC50 ratios of compounds
obtained from the same biofilm inhibition experiment that are
≤10 most likely inhibit biofilm formation via the same
mechanism used to inhibit bacterial growth, thus we have
characterized such compounds as “antibacterial” and not
“biofilm inhibitor” agents.
In biofilm inhibition experiments against S. aureus ATCC
29213, nitroxoline reported an MIC:IC50 ratio of 3.8. The large
differences in MIC:IC50 ratios between quinoline 6 and
nitroxoline (known metal chelator and clinically used

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Larsen, S. D.; Sun, H. PLoS ONE 2012, 7, e47255.
doi:10.1371/journal.pone.0047255.
In conclusion, we have identified several quinolines with potent
biofilm dispersal and antibacterial activity against methicillin-
resistant S. aureus and S. epidermidis using a scaffold hopping
strategy. Our team is currently developing this class biofilm
dispersal agents and biofilm inhibitors against S. aureus and S.
epidermidis. Several of the brominated quinolines that were
identified during the course of these investigations have the
potential to target Staphylococcal biofilms and provide
clinically effective treatment options for patients suffering from
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Acknowledgments
We would like to acknowledge Dr. Judith Johnson (Emerging
Pathogens Institute at the University of Florida) for providing
clinical isolates of S. aureus and S. epidermidis. We would
also like to acknowledge Professor Shouguang Jin for helpful
discussions pertaining to various microtiter experiments. The
authors acknowledge the Office of Research (University of
Florida) for providing a Research Opportunity Seed Fund
Award and the College of Pharmacy for financial support of
this work. A.T.G. and V.M.N. have been awarded Graduate
School Fellowships from the Univ. of Florida. High-resolution
mass spectra were obtained from the Mass Spectrometry
facility in the Chemistry Department at the University of
Florida.
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Supplemental material for the following items can be found in the
Supporting Information document associated with this manuscript,
which include: (1) MIC, biofilm inhibition, biofilm dispersion assay
protocols; (2) supporting data tables with MIC/biofilm assay results;
(3) supporting images of MIC/biofilm assays; (4) synthetic procedures;
(5) NMR spectra for all new compounds/synthesized quinolines.
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