Targeting Biofilm and Quorum Sensing in Pseudomonas aeruginosa by Quercetin, Meloxicam, and Their Potential Synergy with Colistin

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* Corresponding author: Abdulmabod M. M. Omar
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E-mail: abdulmabodomar@yahoo.com
© 2025 by SPC (Sami Publishing Company)
Journal of Medicinal and Chemical Sciences 8 (2025) 136-144
Journal homepage: http://www.jmchemsci.com/
Original Article
Targeting Biofilm and Quorum Sensing in Pseudomonas
aeruginosa by Quercetin, Meloxicam, and Their Potential Synergy
with Colistin
Amira Etman1, Heba M. Abostate1, Dalia A. EL-Damasy1, Hatem Mohamed Newishy2,
Abdulmabod M. M. Omar*3, Ahmed A.NasrEldin Abbas3, Medhat Ali Salah Abd
Elghaffar3, Mohamed Ramadan Zohri3, Mohamed Basiouny Yahia3, Abdullah Mustafa
Ibrahim Gaafar3, Ahmed Abd Elmoez Ali Saad3, Sahar M Radwan4
1Microbiology & Immunology department, Faculty of pharmacy, Egyptian Russian University, Cairo Egypt
2Microbiology & Immunology department, Faculty of medicine (boys), Al-Azhar University, Cairo, Egypt
3Clinical pathology department, Faculty of medicine (boys), Al-Azhar University, Cairo, Egypt
4Microbiology & Immunology department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
A R T I C L E I N F O
A B S T R A C T
Article history
Received: 2024-12-22
Received in revised: 2025-01-08
Accepted: 2025-01-16
Manuscript ID: JMCS-2412-2729
DOI:10.26655/JMCHEMSCI.2025.2.2
Pseudomonas. Aeruginosa (P.aeruginosa) is a vital pathogenic bacterium with
limited therapeutic options. In our previous research, we proved by in silico
studies that quercetin and meloxicam could act as inhibitors for the auto-inducer
molecules of the Quorum sensing system (QS) system LasR and rhlR in
P.aerogenosa. The study aimed to validate the effect of quercetin and meloxicam
on expression of lasR and rhlR genes, to investigate their effect on biofilm forming
ability as an important virulent factor controlled by the (QS) system, and to
examine their combination with colistin antibiotic. Strong biofilm former P.
aeruginosa isolates were selected and PAO1 strain as reference strain, treated
separately by sub-inhibitory of quercetin and meloxicam. Quercetin and
meloxicam were found to have significant inhibitory effect biofilm formation with
down regulation for the QS genes lasR and rhlR. As tested by real time PCR. In
addition, colistin combinations with quercetin or meloxicam were tested by
checkerboard method. This study indicated that both quercetin and meloxicam
have a significant inhibitory effect on biofilm. Hence, they may be used as quorum
sensing inhibitors (QSI). Furthermore, quercetin was found to have a synergetic
effect with colistin.
K E Y W O R D S
Anti-quorum sensing
Biofilm
Pseudomonas aeruginosa
Quercetin
Meloxicam

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137 | P a g e
G R A P H I C A L A B S T R A C T
BACKGROUND AIM METHODOLOGY CONCLUSION
(P.aeruginosa) is a
vital pathogenic
bacterium with
limited therapeutic
options. In our
previous research,
we proved by in silico
studies that
quercetin and
meloxicam could act
as inhibitors for the
auto-inducer
molecules of the
Quorum sensing
system (QS) system
LasR and rhlR in
p.aerogenosa.
The study aimed to
validate the effect
of quercetin and
meloxicam on
expression of lasR
and rhlR genes, also
to investigate their
effect on biofilm
forming ability as an
important virulent
factor controlled by
the (QS) system. In
addition to
examining their
combination with
colistin antibiotic.
Quercetin and
meloxicam were
found to have
significant
inhibitory effect
biofilm formation
with down
regulation for the
QS genes lasR and
rhlR. As tested by
real time PCR.
Strong biofilm
former P.
aeruginosa
isolates were
selected and
PAO1 strain as
reference strain,
treated
separately by sub
inhibitory of
quercetin and
meloxicam
Introduction
P. aeruginosa is an opportunistic Gram negative
pathogen causing serious clinical infections [1].
The highly adaptive and persistent nature of P.
aeruginosa coupled with the frequent use of
antimicrobials sensitize P. aeruginosa to acquire
antimicrobial resistance which could become a
global catastrophe [2].
The absence of new effective antibiotics against
these “superbugs” has led to renewed interest in
reviving older antibiotics that were considered
too toxic for clinical use, in particular, the
polymyxins (colistin), to be used as “last resort”
antimicrobials [3].
As a result, there are many efforts to found novel
approaches other than antibiotic therapy. An
interesting approach depends on targeting
quorum sensing (QS) mechanism [4].
Quorum sensing inhibitors (QSI) is a new
approach for overcoming the antibiotic resistance
dilemma by reducing virulence within bacterial
populations resulting in a less pathogenic
population [5]. Moreover, it helps minimizing the
emergence of antibiotic resistance and favoring
the use of low doses of antibiotics [6].
Compounds with quorum sensing inhibitory
effect including natural and synthetic compounds
have been studied. Quercetin (a dietary flavonoid
found) and meloxicam (one of the NSAIDS) are
examples of these compounds which found to
have quorum sensing inhibitory activity and in
many pathogenic bacteria [7,10].

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Our previous study revealed that both quercetin
and meloxicam have close docking scores with
the reference ligand (Rosmarinic acid) for the
target RhlR, but still quercetin showed better
binding mood inside this pocket [11].
In the current study, we estimated their QSI
efficiency using in vitro experimental methods for
biofilm formation with illustrative electron
microscopy and gene expression by quantitative
real time PCR, and also their additive/ synergistic
effect was estimated by colistin antibiotic.
Materials and Methods
Bacterial Strains, Culture Conditions, and
Antibiogram
P. aeruginosa PAO1 were gifted from
microbiology laboratory of Zagazig University
and 25 clinical isolates were provided from
microbiology laboratory of Al-Azhar University
Hospital. The identification and analysis of
the antimicrobial susceptibility was performed
by the automated system (Micro-scan negative
breakpoint combo panel type 44). Ten MDR
strains out of 25 were selected. All bacterial
cultures were maintained at -20 °C.
Determination of Minimum Inhibitory
Concentration (MIC) for Quercetin, Meloxicam and
Colistin Antibiotic on P. Aeruginosa
Broth micro-dilution method [12] was used to
determine the minimum inhibitory concentration
for quercetin, meloxicam and colistin antibiotic.
Biofilm Formation and Anti-Biofilm Studies
The biofilm formation was determined in the
absence and presence of the two tested
compounds using the modified method of
Stepanovic et al. [13]. Categorization was applied
according to [14]: weak biofilm < 2 negative
control ≤ moderate ≤ 4 negative control < strong
biofilm. The biofilm intensity was compared with
untreated controls for estimating the percentage
inhibition.
Confocal Laser Scanning Microscopy
Scanning electron microscope (SEM) technique
was used for imaging the biofilm formed before
and after each drug treatment, it was used at the
Regional Center for Mycology and Biotechnology
(scanning electron microscope JSM-5500).
Expression of QS Genes
Fluorescence real-time quantitative PCR by a
HERA SYBR Green q pcr kit (WF-1030400X) was
used to investigate the expression of the QS genes
lasR and rhlR for PAO1 and the selected clinical
isolates. The following primers were used to
amplify the lasR and rhlR genes, as well as those
for the reference gene encoding 16S rRN.
lasR: Forward CTGTGGATGCTCAAGGACTAC,
Reverse ACCGAACTTCCGCCGAAT/ rhlR: Forward
GAAATCGCCATCATCCTG, Reverse
CGTCGAACTTCTTCTGGA/16srRNA: Forward
CCTACGGGAGGCAGCAG, Reverse
ATTACCGCGGCTGCTGGCA (Obtained from Alpha
DNA, Montreal, Quebec H3C 0J7
http:/www.alphadna.com). The 2−ΔΔCT method
was used to analyze the relative changes in gene
expression [15].
Drug Synergy Experiments and Fractional
Inhibitory Concentration
Checkerboard method was used for detecting the
combinational effect of (quercetin/ meloxicam)
on Colistin antibiotic at different fractional MIC
concentrations. The fractional inhibitory
concentrations (FICs) and FIC index (FICi) were
calculated [16]. Synergy was defined based on the
FICi and the interactions were classified as
follows: FICi ≤ 0.5 as synergistic; >0.5 to ≤ 1 as an
additive; and FICi>1 as antagonistic [17].
Statistical Analysis
Recorded data were analyzed using the statistical
package for social sciences, version 20.0 (SPSS
Inc., Chicago, Illinois, USA). Quantitative data
were expressed as mean± standard deviation
(SD). A one-way analysis of variance (ANOVA)
when comparing between more than two means,
Tukey's test was also used for multiple
comparisons between different variables, p-value
<0.05 was considered significant.

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(A) (B) (C)
Figure 1: Biofilm formation by P. aeruginosa (PAO1) using scanning electron microscope JSM-5500
(A) PAO1 biofilm without any treatment, (B) PAO1biofilm treated with meloxicam at 15.62 µg/ml, and
(C) PAO1 biofilm treated with quercetin at 93.75 µg/ml biofilm
Table 1: The percentages of reduction in biofilm formation at different quercetin concentrations
Quercetin concentration
11.71 (µg/ml)
23.4 (µg/ml)
46.87
(µg/ml)
93.75
(µg/ml)
187.5
(µg/ml)
Standard Strain
Pao1
Mean
23.800A
43.145A
54.210B
59.986BC
72.790BC
±SEM
4.346
2.868
0.557
1.025
0.502
Clinical Strain
P1
Mean
6.838BC
12.820D
18.301E
64.254AB
71.393BC
±SEM
0.447
2.322
0.963
2.469
1.106
P2
Mean
11.166BC
49.979A
63.370A
71.570A
78.451AB
±SEM
3.486
1.059
0.526
0.823
2.448
P3
Mean
16.311AB
31.473B
49.425B
54.297C
80.898A
±SEM
0.790
4.212
0.284
2.907
1.785
P4
Mean
7.188BC
18.783CD
40.232C
61.333BC
66.087CDE
±SEM
0.307
1.004
0.900
0.613
0.531
P5
Mean
5.304BC
22.001BCD
37.553CD
57.746BC
66.847CD
±SEM
1.246
0.336
2.999
1.390
1.418
P6
Mean
2.276C
24.797BC
40.813C
54.797C
62.195DE
±SEM
0.215
1.198
0.494
1.833
2.305
P8
Mean
8.535BC
21.102CD
33.602D
54.839C
58.804E
±SEM
2.986
0.574
0.374
1.829
0.941
ANOVA test
F
8.964
36.632
127.742
11.065
24.515
p-value
<0.001**
<0.001**
<0.001**
<0.001**
<0.001**
Different capital letters indicate significant difference at (p<0.05) among means in the same column
using Tukey's test, multiple range, and multiple F tests; p-value <0.05 significant.
Results
Antibiotic Sensitivity Testing
Antimicrobial sensitivity testing was performed
using Micro-scan technique for P. aeruginosa
clinical isolates, it was found that among 25
clinical isolates, and only 10 were found to be
MDR.

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Minimum Inhibitory Concentration (MIC)
The MIC of quercetin was ≥ 375µg/ml, while MIC
of meloxicam was ≥ 31.25 µg/ml. The anti-biofilm
effect was tested at different sub-inhibitory
concentrations of the two compounds. All the
clinical isolates included in this study and also
the standard PAO1 were sensitive to Colistin. The
highest MICs were to the standard PAO1 =2 mg/L
and one of the clinical isolates P1 MIC was =1
mg/L.
Biofilm Formation and Anti-Biofilm Activity
Seven out of the ten MDR P. aeruginosa strains
were strong biofilm former and only 3 were
moderate and none were weak. The effect of the
quercetin and meloxicam on QS controlled
different virulence factors was tested in those 7
MDR, strong biofilm former P. aeruginosa strains
and PAO1 strain. It was found that the quercetin
concentration 93.75 µg/ml is the lowest
concentration causing more than 50% (54% to
71%) reduction in the biofilm development with
the standard strain PAO1 and the clinical isolates
while at meloxicam concentration 15.625 µg/ml,
the percentage of reduction ranged from 33% to
65%, as indicated in Figure 1 and Tables 1 and 2.
Table 2: The means of BIOFILM absorbance readings (590 nm) at different meloxicam concentrations
with P.aeruginosa standard strain and clinical strains
Meloxicam concentration
Positiv
e
contro
l
Concentration
Negativ
e
control
ANOVA test
1.9
(µg/ml
)
3.9
(µg/ml
)
7.812
(µg/ml
)
15.625
(µg/ml
)
F
P-value
Standard
Strain
Pao
1
Mea
n
0.488A
0.486A
0.370B
0.225C
0.214C
0.093D
423.621
<0.001*
*
±SE
M
0.007
0.001
0.014
0.008
0.006
0.002
Clinical Strain
P1
Mea
n
0.546A
0.463B
0.404B
0.407B
0.246C
0.073D
158.251
<0.001*
*
±SE
M
0.011
0.013
0.003
0.002
0.013
0.025
P2
Mea
n
0.878A
0.794B
0.649C
0.590D
0.306E
0.019F
735.688
<0.001*
*
±SE
M
0.016
0.005
0.023
0.005
0.007
0.001
P3
Mea
n
0.691A
0.616B
0.554C
0.510C
0.458D
0.054E
460.951
<0.001*
*
±SE
M
0.002
0.013
0.007
0.004
0.015
0.014
P4
Mea
n
0.580A
0.530B
0.424C
0.372D
0.217E
0.087F
919.938
<0.001*
*
±SE
M
0.002
0.004
0.002
0.012
0.006
0.004
P5
Mea
n
0.595A
0.527B
0.427C
0.311D
0.208E
0.090F
1938.83
8
<0.001*
*
±SE
M
0.002
0.004
0.004
0.007
0.001
0.005
P6
Mea
n
0.410A
0.395A
B
0.376B
0.289C
0.210D
0.092E
735.515
<0.001*
*
±SE
M
0.005
0.001
0.004
0.008
0.004
0.003
P8
Mea
n
0.496A
0.482A
0.376B
0.315C
0.277D
0.089E
375.287
<0.001*
*
±SE
M
0.008
0.005
0.008
0.007
0.012
0.005
Different capital letters indicate significant difference at (p<0.05) among means in the same row using
Tukey's test, multiple range, and multiple F tests; p-value <0.05 significant.

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Scanning Electron Microscope (SEM)
The previous results were evidenced using
electron microscope and it was found that the
biofilm formed after 48 h incubation shows
biofilm formation with and without treatment
with the two drugs. Quercetin was found with a
greater anti-biofilm effect than meloxicam where
the cell cluster was weaker with lower
extracellular polymeric substance (EPS)
formation and large gaps.
Gene Expression
Real time PCR was performed for PAO1 standard
strain, P1 and P3 were the examples of the
clinical isolates. Quantitative analysis for both
genes (lasR and rhlR) were performed before and
after treatment with the selected drugs at the
sub-inhibitory concentration and found with
more than 50% inhibitory effect on biofilm
formation using real-time PCR. The two drugs
resulted in downregulation (2-ΔΔCT value <1) of
lasR gene occurred in all tested strains where
quercetin had better effect than meloxicam.
Regarding their effect on rhlR expression
quercetin caused downregulation in all tested
samples while meloxicam caused downregulation
in PAO1 and P1 and it surprisingly caused
upregulation in the clinical isolate, as shown in
Figure 2 and Table 3.
Figure 2: (2-ΔΔCT value) of lasR and rhlR genes for PAO1, P1, and P3 clinical isolate when treated with
quercetin (93.75 µg/ml) and meloxicam (15.62 µg/ml)
Table 3: 2-ΔΔCT values of lasR and rhlR genes of PAO1, P1, and P3 clinical isolates upon treatment
Gene expression (2-ΔΔCT)
Standard strain
Clinical strain
Clinical strain
PAO1
P1
P3**
lasR
rhlR
lasR
rhlR
lasR
rhlR
Control
1.0000A
1.0000A
1.0000A
1.0000A
1.0000A
1.0000A
Quercitin Conc. At 93.75
(µg/ml)
0.1376C
0.1324C
0.0263C
0.0456B
0.6029
0.8882
Meloxicam Conc. At 15.62
(µg/ml)
0.2683B
0.3126B
0.0386B
0.0440B
0.8937
1.159
Different capital letters indicate significant difference at (p<0.05) among means in the same column
using Tukey’s test, multiple range, and multiple F tests; p-value <0.05 significant.
Drug Synergy Study and Fractional Inhibitory
Concentration
The PAO1 and the clinical isolate P1 strains were
chosen to evaluate the combinational effect of the

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tested drugs with Colistin by Checkerboard
method as they had the highest MICs. It was
found that Meloxicam showed an additive effect
when combined with ½ MIC or ¼ MIC of colistin,
while quercetin showed a good synergistic effect
in combination with (¼ MIC).
Discussion
Pseudomonas aeruginosa was placed on the top of
the priority pathogen list (critical) by World
Health Organization (WHO) for prioritizing the
new antibiotic development against MDR
pathogens [18], in the present study, after
preforming the antibiotic susceptibility test for
the clinical isolates, 10 isolates were selected
(MDR) (Multiple drug-resistant).
The MIC of quercetin against Pseudomonas
aeruginosa strains was ≥ 375 µg/ml. In previous
studies, the MIC of quercetin against the
Pseudomonas aeruginosa strains showed to be
greater than 256 µg/ml [19] and 500 μg/mL [20]
while the MIC of meloxicam against Pseudomonas
aeruginosa strains was ≥ 31.25 µg/ml, which
came in accordance with result for PAO1 in a
previous study [21].
Regarding the effect of both drugs on biofilm
formation, our study revealed that concentration
93.75 µg/ml is the lowest concentration causing
more than 50% (54% to 70%) reduction in the
biofilm development. In agreement with our
results the Anti-biofilm effects of quercetin on P.
aeruginosa using different concentrations was
reported by some studies [19,21,22] and was
explained by QS inhibition due to blocking of
protein synthesis.
Quantitative expression analysis for both RNA
genes (lasR and rhlR) Showed downregulation of
both genes upon treatment with quercetin and
meloxicam. Quercetin has better effect as it
causes (86% and 97%) reduction in lasR
expression and (86% and 95%) reduction in rhlR
expression in PAO1 and P1, respectively, while
meloxicam at 15.62 µg/ml cause (73% and 96%)
reduction in lasR expression and (68% and 95%)
reduction in rhlR expression in PAO1 and P1,
respectively. Previous research studied the effect
of quercetin on lasR and rhR systems and it was
found that 16 µg/ml of quercetin could
significantly reduce the expression of LasR by
68% and rhlR by 50% [19]. Likewise, a previous
study indicated that meloxicam could cause a
59% reduction in lasR expression and a 51%
reduction in rhlR expression at concentration of
15.63 µg/ml [21].
The clinical isolate P3 showed different results, as
treatment with quercetin caused 40% reduction
in lasR expression and only 12% reduction in
rhlR expression. While meloxicam caused 11%
reduction in lasR expression and it surprisingly
caused upregulation in rhlR expression by 15%.
In a previous study, the combinatorial efficacy of
antibiotics with quercetin was tested against P.
aeruginosa isolates and showed that quercetin at
125 µg/mL had a synergistic effect with ½ × MIC
or ¼ × MIC of many the antibiotics
(levofloxacin,tobramycin, amikacin, and
gentamycin) against all the tested strains [20].
In this study, we aimed to decrease the MIC of
colistin to reduce its cytotoxic effect and the risk
of building up a bacterial resistance against it by
testing its combinations with quercetin or
meloxicam. Meloxicam did not show any
synergistic effect when combined with colistin, it
only has an additive effect while quercetin
showed a good synergistic effect. Therefore,
quercetin/colistin combination can be considered
as an effective and less toxic solution for MDR
treatment. Apart from anti-quorum sensing
effect, quercetin can alter the bacterial cell wall
ultrastructure and cell membrane integrity of the
bacteria [23]. The increase in cell membrane
permeability makes the combination treatment
more effective.
Conclusion
In sum, this study demonstrates that both
quercetin and meloxicam can cause significant
reduction in biofilm formation. Also, both drugs
caused downregulation in some quorum sensing
genes (lasR and rhlR). Further study is
recommended to investigate the upregulation of
gene rhlR in the clinical isolate strain p
Acknowledgments
The authors would like to thank the Teaching
Assistant/ Mohammed Reda for his great support
in coordinating and editing this work.

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Funding
This study was not funded by any specific grant
from funding agencies in the public, commercial,
or not-for-profit sectors.
Disclosure Statement
The authors declare that there are no conflicts of
interest in this study.
Ethics Approval
Not applicable.
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Data Availability
All data generated or analyzed during this study
are included in this published article.
Authors' Contributions
First and second authors were equally
participating in whole work preparations , All
other authors participated in practical work ,
statistical data, reading , and approving the final
manuscript.
ORCID
Abdulmabod M. M. Omar
https://orcid.org/0009-0000-5670-3555
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HOW TO CITE THIS ARTICLE
Amira Etman, Heba M. Abostate, Dalia A. EL-Damasy, Hatem Mohamed Newishy, Abdulmabod M. M. Omar, Ahmed
A.NasrEldin Abbas, Medhat Ali Salah Abd Elghaffar, Mohamed Ramadan Zohri, Mohamed Basiouny Yahia, Abdullah
Mustafa Ibrahim Gaafar, Ahmed Abd Elmoez Ali Saad, Sahar M Radwan, Targeting Biofilm and Quorum Sensing in
Pseudomonas aeruginosa by Quercetin, Meloxicam, and Their Potential Synergy with Colistin . J. Med. Chem. Sci., 2025,
8(2) 136-144
DOI: https://doi.org/10.26655/JMCHEMSCI.2025.2.2
URL: https://www.jmchemsci.com/article_213729.html