Critical ReviewsTM in Eukaryotic Gene Expression, 29(5):377 – 385 (2019)

Review of Anti-Bacterial Activities of Curcumin

against Pseudomonas aeruginosa
Zohreh Neyestani,a Seyed Ali Ebrahimi,b Anahita Ghazaghi,b Amin Jalili,c
Amirhossein Sahebkar,d,e,f,* & Hamid Reza Rahimid,*
a
Department of Microbiology, Faculty of Sciences, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran;
b
Student Research Committee, Islamic Azad University, Mashhad branch, Mashhad, Iran; cDepartment of Medical
Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; dNeurogenic
Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; eBiotechnology Research
Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; fSchool of
Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
*Address all correspondence to: Amirhosein Sahebkar, Tel.: +985138002288, E-mail: sahebkara@mums.ac.ir; amir_saheb2000@yahoo.com; and
Hamid Reza Rahimi, Tel.: +985138002288, E-mail: rahimihr@mums.ac.ir

ABSTRACT: The prevention and pharmacotherapy of infectious diseases are of great importance. Among others, infec-
tions caused by Pseudomonas aeruginosa have a high mortality rate. This bacterium is the third most common cause of
nosocomial infections, and characteristics such as multiple virulence factors, ability to survive, environmental spread,
and resistance to antibiotics have made it a potential pathogen, especially for people with compromised immune systems.
Considering bacterial resistance to current medications, high cost, and side effects, the need to provide new and effective
therapies is highlighted. Curcumin is a dietary polyphenolic compound that has a wide range of therapeutic properties,
including antibacterial effects. It has been the subject of increasing research exploring its potential utility in infectious
diseases. In this review, the antibacterial effects of curcumin against Pseudomonas aeruginosa are discussed.

KEY WORDS: bacterial infections, Pseudomonas aeruginosa, curcumin, quorum sensing

I. INTRODUCTION attributed to curcumin, owing to its abundance in the

Curcumin is the main active ingredient of turmeric
(Curcuma longa L.), imparting the orange-yellow
color of this spice.1 Turmeric has a long repu-
tation of therapeutic applications in several tra-
ditional systems of medicine, including Iranian
traditional medicine, in which topical use is rec-
ommended for reducing joint pain and swelling
because of the anti-inflammatory effects of the
plant.2 Modern phytopharmacological investiga-
tions have revealed that many of the putative ther-
apeutic properties of turmeric are due to curcumin.
Depending on the origin and quality of the plant rhi-
zome, curcumin constitutes 2% to 8% of turmeric.
Turmeric contains three different structural ana-
logs that are collectively known as curcuminoids,
including curcumin, demethoxycurcumin, and
bisdemethoxycurcumin.3,4
Although it is not clear that all existing analogs
have the same pharmacological potency, in most
cases the therapeutic properties of curcuminoids are
plant. Generally, using a combination of curcumi-
noids provides better effects compared to curcumin
alone.5 Several studies have been conducted on the
biological effects of curcumin and curcuminoids in
recent years. More than 3,000 studies have shown
their numerous pharmacological effects, including
antioxidant, antifungal, antiviral, anti-inflamma-
tory, antiproliferative, proapoptotic, and especially
antibacterial (Fig. 1).6–9 In addition, the therapeutic
value of curcuminoids has been reported against
numerous pathological conditions and human dis-
eases, such as neurodegenerative diseases, arthritis,
diabetes, psoriasis, Alzheimer’s disease, depression,
AIDS, multiple sclerosis, allergies, inflammatory
bowel disease, nephrotoxicity, cardiovascular dis-
ease, and cancer.10
Owing to its antimicrobial activity and safety
of use even at high doses (12 g/day), curcumin has
been evaluated in some studies and has been used
as a structural lead for designing new antimicrobial
agents with enhanced antimicrobial effects.6

1045-4403/19/$35.00 © 2019 by Begell House, Inc. www.begellhouse.com377

378 Neyestani et al.

FIG. 1: Antimicrobial and biological functions of curcumin

II. CURCUMIN at 183°C. Turmeric grows naturally throughout the

Curcumin was discovered about two centuries ago,
and for the first time, in 1815, Vogel and Pelletier iso-
lated it from the turmeric plant rhizome in the form
of an impure colored compound.11 In 1842, Vogel
purified curcumin; however, its formula remained
unknown.12 In 1910, Milobedzka et al. identified the
structure and chemical formula of curcumin, and in
1913 he and Lampe synthesized it.13 In 1953, Sri-
nivasan identified and isolated components of cur-
cuminoids using chromatography.14
The chemical formula of curcumin is
1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadi-
ene-3,5-dione) (Fig. 2). It is insoluble in water and
ether, but soluble in ethanol, dimethyl sulfoxide,
and acetone.15 Its molecular formula is C21H20O,
and its molecular weight is 368.37 g/mol.12 It melts
Indian subcontinent and in tropical countries, espe-
cially in Southeast Asia and China, and has been
used in traditional medicine for thousands of years.16
Since the free form of curcumin has low bio-
availability, various strategies have been developed
to improve its bioavailability, leading to the produc-
tion of curcumin nanomicelles and nanoparticles,17
which have been shown to significantly enhance
curcumin bioavailability.18 Research has shown that
curcumin can protect the liver against alcoholic liver
disease (ALD) by inhibiting the activation of sev-
eral NF-κB–reactive genes that are activated during
alcohol use.19 It has also been shown that this com-
pound reduces HbA1c levels and improves glyce-
mic control in type 2 diabetes.20
In one study, oral administration of curcumin
for 1 month (1 g/day) reduced the concentration of

FIG. 2: Chemical structure of curcumin

Critical ReviewsTM in Eukaryotic Gene Expression

Activities of Curcumin against Pseudomonas aeruginosa379
triglycerides in obese people.21 Other studies have
shown that nano-curcumin can suppress the growth
of esophageal squamous carcinoma cells, which
may be associated with decreased regulation of the
cyclin D1 gene.22 For reasons such as these, accord-
ing to its antimicrobial effects, its diverse therapeu-
tic properties, and its low side effects,23 curcumin
is used in the prevention and treatment of various
disorders.
III. CURCUMIN’S ANTIBACTERIAL FUNCTION
For more than 50 years, extensive research has
been carried out to obtain antibiotics from different
sources, as bacterial infections are one of the most
important infectious diseases. Although progress
has been made in developing antibacterial agents,
the demand to find new ones still exists due to
the emergence of multidrug-resistant bacteria.24
Increased drug resistance and multidrug resistant
strains arising from the arbitrary use of antibiotics
and, on the other hand, the intrinsic and acquired
resistance of bacteria including P. aeruginosa, which
is resistant to three antibiotic families25—all of these
factors have made controlling hospital infections
difficult.26
In vitro studies have shown the antimicro-
bial potential of curcumin against a wide range of
microorganisms, including fungi,27 as well as sev-
eral Gram-positive and Gram-negative bacteria.25 In
this regard, antimicrobial evaluation of the aqueous
extract of the turmeric rhizome has shown that the
minimum inhibitory concentration is 4 to 16 g/L
and the minimum bactericidal concentration is 16
to 32 g/L against Staphylococcus epidermidis ATCC
12228, Staphylococcus aureus ATCC 25923, Kleb-
siella pneumoniae ATCC 10031, and Escherichia
coli ATCC 25922. Furthermore, hexane and metha-
nol extracts of this plant showed antibacterial effects
against 13 bacteria, including a number of Vibrio,
Staphylococcus, and Streptococcus species.28 In
addition, it was shown that adding 0.3% w/v of
aqueous extract of turmeric to cheese reduces the
presence Salmonella typhimurium, P. aeruginosa,
and Escherichia coli bacteria 0157:H7.29
Curcumin showed significant antibacterial
activity, with MIC values between 5 and 50 μg/ml
Volume 29, Issue 5, 2019
against H. pylori.30 In vitro studies on the antibac-
terial effects of three new curcumin compounds—
indium curcumin, indium diacetylcurcumin, and
diacetylcurcumin—against S. aureus, S. epider-
midis, E. coli, and P. aeruginosa showed that indium
curcumin has better antibacterial effects than cur-
cumin itself against the tested bacteria while diace-
tylcurcumin has none.31 These results indicated that
there might be a promising antimicrobial potential
in different curcumin derivatives.
Given the emergence of drug-resistant bacte-
ria, it is essential to study the synergistic effects of
antibiotics in combination with herbal derivatives to
develop antimicrobial strategies with a wide range
of activities and lower side effects.32 Because com-
binational therapies increase the likelihood that the
infectious pathogen will be susceptible to at least one
of the components of the drug, they can overcome
drug-resistant strains.33 Using two or more factors,
they also have synergistic effects that increase effi-
ciency or reduce the dosage while maintaining effi-
cacy.34 In this regard, curcumin showed synergistic
effects in combination with some antibiotics, includ-
ing ampicillin, oxacillin, and norfloxacin, against
methicillin-resistant S. aureus.35 Additionally, the
combination of curcumin with cobalt nanoparticles
showed increased antimicrobial activity against E.
coli.36 Curcumin-impregnated silver nanocompos-
ite films also produced stronger antibacterial effects
against E. coli.37 These results show that curcumin
is a natural antioxidant and anti-inflammatory com-
pound with high efficacy and low cytotoxicity,
making it a potentially ideal candidate for use in
combination therapy against bacterial infections.33
IV. P. AERUGINOSA AND ITS
DRUG-RESISTANCE MECHANISMS
P. aeruginosa is known to be a Gram-negative,
drug-resistant, opportunistic pathogen. Its multi-
drug resistance is the result of a set of factors, the
entirety of which is beyond the scope of this review.
Rather, we highlight only those associated with the
antimicrobial function of curcumin: low permeable
outer membrane, expression of efflux pumps, and
a recently discovered phenomenon called quorum
sensing, which is associated with biofilm formation.
380 Neyestani et al.
The outer membrane of Gram-negative bacteria
plays a crucial role as a permeability barrier that is
dependent on solute size. The antimicrobial resis-
tance of P. aeruginosa has been linked to the low
permeability of its outer membrane. In two studies
involving purified porins, Hancock et al. showed
that the P. aeruginosa porin produces a significantly
larger pore than the pores of some intestinal bacte-
ria such as S. typhimurium and E. coli.38,39 Increased
sensitivity to antimicrobials was found after damage
to or removal of the bacteria’s outer membrane.40
Yoshimura and Nikaido determined the permeabil-
ity of P. aeruginosa’s outer membrane directly as
about 100-fold lower than the outer membrane of
E. coli.41 These findings show that achieving high
concentrations of antimicrobials in P. aeruginosa is
difficult because its low permeability contributes to
its antimicrobial resistance.
Four multidrug efflux pumps are characterized
in P. aeruginosa: MexAB-OprM, MexEF-OprN,
MexCD-OprJ, and MexXY-OprM. Efflux pumps
MexAB-OprM, MexEF-OprN, and MexCD-OprJ
provide resistance to β-lactam antibiotics. Moreover,
overexpression of MexEF-OprN and MexCD-OprJ
enables the bacterium to resist fluoroquinolones, and
overexpression of MexXY-OprM enhances its resis-
tance to aminoglycoside.42 Through these pumps,
the bacterium disposes of antimicrobial agents and
other toxic substances, and causes difficult-to-treat,
life-threatening infections.43 If these efflux pumps
are blocked or inhibited, increasing the drug con-
centration in the bacteria can produce a sufficient
and lethal dosage.
Quorum sensing is a language that allows bac-
teria to manifest multicellular behaviors and engage
in cell-to-cell communication. Using this system,
the bacterium determines its population density
and so regulates the expression of particular genes.
Bacteria use quorum sensing to regulate a variety
of physiological functions, including virulence,
conjugation, motility, and biofilm formation.44 Bio-
films are an aggregate of microorganisms within a
self-produced matrix of extracellular polymeric sub-
stances that adhere to each other or to a surface.45
They contribute to the chronicity and recurrence of
infection by inhibiting the penetration of a drug into
the extracellular matrix. The end result is prolonged
hospitalization, long-term costs, and failure of
treatment.29,46
V. CURCUMIN’S ANTIBACTERIAL FUNCTION
AGAINST P. AERUGINOSA
A number of recent studies have confirmed the poten-
tial of curcumin against P. aeruginosa (Table 1).
One study carried out in 2014 reported that the bac-
tericidal function of curcumin against P. aeruginosa
increased proportionally to its concentration and that
100 μM of curcumin caused 100% death of the bac-
terium in two hours.33 A similar in vivo animal study
showed that chitosan tri-polyphosphate nanoparti-
cles containing curcumin significantly suppressed
the progression of P. aeruginosa infection in mice
while chitosan tri-polyphosphate alone was unable
to do so.34 Given these results, what is the under-
ling mechanism of the antimicrobial function of cur-
cumin from a microbiological point of view?
A recent study demonstrated that the bacteri-
cidal activity of curcumin is associated with dam-
age to the bacterial membrane. The integrity of P.
aeruginosa, E. coli, S. aureus, and E. faecalis mem-
branes was checked by two differential permeabi-
lization–indicating fluorescent probes: propidium
iodide and calcein. Membrane leakage in all four
bacteria exposed to curcumin was observed.33
As aforementioned, efflux pumps are responsi-
ble for the discharge of antibiotics from P. aerugi-
nosa. It has been shown that curcumin inhibits their
expression and thus overcomes drug resistance. Negi
et al. used 30 multidrug-resistant strains of P. aeru-
ginosa derived from clinical isolates and derived
MIC values for curcumin (50 mg/L) with and with-
out antibiotics. They observed significant reduc-
tions in MIC for curcumin combined with selected
antimicrobial agents in 30% of multidrug-resistant
isolates of P. aeruginosa but no change in MIC for
curcumin alone, indicating curcumin’s efflux pump
inhibitory activity.47
After determining the role of quorum sensing
in various vital processes, including expression of
pathogenicity factors and the development of resis-
tant bacterial infections, efforts were made to use it
to directly target pathogenic factors as a solution to
antibiotic resistance.48 In this regard, various studies
Critical ReviewsTM in Eukaryotic Gene Expression
Activities of Curcumin against Pseudomonas aeruginosa381

TABLE 1: Studies evaluating curcumin’s antimicrobial effects against P. aeruginosa

Study Year Study type Effect Ref
Tajbakhsh et al. 2008 In vitro Indium diacetylcurcumin activity against P. aeruginosa 31
Rudrappa and Bais 2008 In vivo/in vitro Reduced expression of genes involved in quorum sensing and 25
biofilm formation in P. aeruginosa
Niamsa and Sittiwet 2009 In vitro No significant inhibitory effect against P. aeruginosa 26
Hosny et al. 2011 In vitro Addition of 0.3% w/v of aqueous extract of turmeric to cheese 29
decreased P. aeruginosa
Mirnejad et al. 2014 In vivo Curcumin-loaded chitosan-TPP nanoparticles inhibited S. 34
aureus and P. aeruginosa growth
Packiavathy et al. 2014 In vitro Inhibition of P. aeruginosa biofilm formation possibly by 57
interfering with quorum sensing
Negi et al. 2014 In vitro Significant reduction in MIC after adding curcumin with 47
antimicrobials in 30% of multidrug-resistant isolates of P.
aeruginosa, indicating efflux pump inhibitor activity
Tyagi et al. 2015 In vitro 100% inhibition of P. aeruginosa membrane leakage of 33
bacteria
Bahari et al. 2017 In vitro Significant decrease in MIC of azithromycin and gentamicin, 56
indicating synergism against P. aeruginosa quorum sensing

have shown that curcumin inhibits quorum sensing
in P. aeruginosa by affecting pathogenicity factors,29
in this way preventing the formation of bacterial
biofilms. Many genes in P. aeruginosa that play a
role in its pathogenicity are regulated and expressed
by quorum sensing—for instance, lasI, lasR, rhlI,
and rhlR and the human lasB, apr, and rhlAB house-
keeping genes.50
There are two complete quorum-sensing systems
in P. aeruginosa: (1) las, which includes the lasR and
lasI transcription-activating genes that regulate elas-
tase, exotoxin A, and alkaline protease production;
and (2) rhl, which encompasses the rhlR and rhlI
genes that regulate the production of rhamnolipid,
alkaline protease, elastase, cyanide, and pyocyanin.51
rhlR and rhlI produce transcription-regulating
proteins that activate virulence genes.52 The las
system is responsible for the transcription and
expression of other virulence factors and pyocy-
anin pigment, and for the production of biofilms
that contribute to bacterial invasion of host cells
and resistance to host immunity.50,53 Because of
the different virulence genes in P. aeruginosa and
because of the importance of quorum-sensing genes,
the frequency of these genes is not well defined and
differing reports are controversial. However, one
study reported the highest frequency for LasI (60%)
and LasR (48.3%). Aghamollaei et al. reported
the frequency of the quorum-sensing LasI gene as
46.5%.46 In this regard, it has been shown that there
is a correlation between defective virulence factor
production and increased sensitivity to antibiotics.54
Therefore, the quorum-sensing process is a suitable
target for the development of anti-quorum-sensing
therapies independent of antibiotics, which are con-
sidered an effective strategy to fight against bacte-
rial infections.
Since curcumin has shown synergic effects
when combined with antibiotics against P. aerugi-
nosa,55 its inhibitory effect with azithromycin and
gentamicin against the bacterium’s quorum-sens-
ing signal transduction system was investigated.
The results showed a significant reduction in the
pathogenicity associated with quorum sensing, such
as biofilm formation and motility with azithromy-
cin, gentamicin, and curcumin in 1.4 and 1.16 MIC
alone and in combination. It was also reported that
the combination of azithromycin and curcumin at a
concentration of 1.4 MIC had the highest inhibitory
effect on biofilm formation and motility.56

Volume 29, Issue 5, 2019

382 Neyestani et al.
Measurement of expression of quorum sensing–
regulating genes, including lasI, laR, rhlI, and rhlR,
showed that azithromycin, gentamicin, and cur-
cumin in 1.4 MIC alone and in combination inhibits
quorum sensing at the transcription level. RT-PCR
analysis showed that, compared to nonintervention
bacteria, the relative expression of lasR decreased
significantly in the presence of azithromycin alone
and decreased by 80% with the addition of cur-
cumin. Azithromycin alone and in combination with
curcumin reduced the expression of rhlI by 60% and
67%, respectively.56
It has been shown that the combination of cur-
cumin and antibiotics such as azithromycin and
gentamicin exhibits synergistic effects against quo-
rum sensing in P. aeruginosa.56 Packiavathy et al.
reported that curcumin consistently inhibited the for-
mation of E. coli biofilms and P. aeruginosa PAO1,
Serratia marcescens, and Proteus mirabilis by sup-
pressing the signal cascade of the quorum-sensing
process (Fig. 3).57
Finally, it should be noted that one of the cur-
rent issues surrounding the antimicrobial effects of
curcumin is the lack of clinical studies. So far no
interventional studies have been carried out on the
FIG. 3: Antibacterial function of curcumin against Pseu-
domonas aeruginosa
antimicrobial effects of curcumin against P. aerugi-
nosa. The low bioavailability and variable pharma-
cokinetics of different oral formulations of curcumin
may represent important limitations in the design
and conduct of interventional studies. However, in
recent years, new pharmacological techniques have
largely contributed to solving the bioavailability
problem. In this case, the drug Meriva is a good
example. Meriva is a proprietary curcumin-phos-
phatidylcholine phytosome complex that has shown
29-fold higher absorption than ordinary curcumin.58
Another example is SinaCurcumin, in which cur-
cumin is within the hydrophobic section of the
nanomicelles. These nanomicelles increase the sol-
ubility of curcumin in water and thus increase its
absorption.20 Given the promising data on the poten-
tial antimicrobial function of curcumin, we suggest
that researchers carry out randomized clinical trials
addressing this issue.
VI. CONCLUSION
Curcumin, the active ingredient in turmeric, has
been an object of study for scientists for many years
because of its unique biological and therapeutic
properties.59 As shown by the research discussed
in this review, curcumin has different antibacterial
properties against various types of Gram-negative
bacteria, in particular P. aeruginosa, which is the
focus of this paper.
The results of various studies show that the
expression of most genes producing P. aeruginosa
pathogenic factors is regulated by a gene system
called quorum sensing. Curcumin can inhibit quo-
rum sensing by influencing its pathogenicity fac-
tors.29 In doing so, it inhibits biofilm growth,29
reestablishing bacterial sensitivity to antibiotics.60
This has led to the use of curcumin as an effective
therapy in combination with antibiotics.6 Results
show that curcumin has the ability to overcome drug
resistance by inhibiting the expression of efflux
pumps in P. aeruginosa, bestowing promise for its
use in the treatment of multidrug-resistant bacterial
infections.6,53 Curcumin should therefore be consid-
ered a valuable recruit in the battle against bacterial
infections caused by P. aeruginosa, though more
comprehensive studies are needed to confirm this.
Critical ReviewsTM in Eukaryotic Gene Expression
Activities of Curcumin against Pseudomonas aeruginosa383
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