Journal of Biomaterials and Nanobiotechnology, 2012, 3, 519-527 Published Online October 2012 (
Overview of Multidrug-Resistant Pseudomonas aerugin osa
and Novel Therapeutic Approaches
Marilyn Porras-Gómez1, José Vega-Baudrit1, Santiago Núñez-Corrales2
1National Nanotechnology Laboratory LANOTEC, National Center for Advanced Technology CeNAT, San José, Costa Rica;
2E-Science Research Program, Costa Rican Institute of Technology, Cartago, Costa Rica.
Received July 18th, 2012; revised August 23rd, 2012; accepted September 2nd, 2012
Gram-negative bacilli Pseudomonas aeruginosa is an important pathogen in hospitalized patients, contributing to their
morbidity and mortality due to its multiple resistance mechanisms. Therefore, as therapeutic options become restricted,
the search for new agents is a priority. Latterly an accelerated increase in frequency of multidrug-resistant clinical
strains has severely limited the availability of therapeutic options. Several in vitro and in vivo studies evaluating the
efficacy of different antimicrobials agents and development of vaccines against P. aeruginosa have been reported as
novel approaches, such as inhibition of virulence factor expression or inhibition of their metabolic pathways.
Keywords: Bacilli; Gram-Negative; Pseudomonas aeruginosa; Multidrug Resistance; Pathogen; Resistance
1. Introduction
Pseudomonas aeruginosa is an opportunistic pathogen
that may cause severe invasive diseases in critically ill
patients. The frequency of infections caused by them is
increasing and multidrug-resistant (MDR) strains, resis-
tant to almost all available antimicrobials, are emerging
in hospitalized patients.
Because of its ubiquitous nature, ability to survive in
moist environments, and innate resistance to many anti-
biotics and antiseptics, P. aeruginosa is a common
pathogen in hospitals and particularly in intensive care
units. It has become increasingly clear that resistance
development in P. aeruginosa is multifactorial, with mu-
tations in genes encoding porins, efflux pumps, penicil-
lin-binding proteins, and chromosomal β-lactamase, all
contributing to resistance to β-lactams, carbapenems, am-
inoglycosides, and fluoroquinolones [1]. Strains of P.
aeruginosa are the cause of several diseases in nosoco-
mial environments, predominantly pneumonia, bactere-
mia, meningitis, urinary tract infections, as well as skin
and soft-tissue infections [2]. Due to the emergence of
MDR pathogens, it is of ultimate importance to develop
new antimicrobial drugs.
P. aeruginosa has been characterized as one of the
most versatile microbial organisms, with a wide span of
habitats including soil, disinfectant solution and jet plane
fuel [3]. Low permeability of its outer membrane by a
complex set of efflux pump systems and secretion of
alginate during biofilm formation are major factors that
allow the pathogen to become highly virulent and resis-
tant to multiple antibiotic agents. Adding to these factors,
other baterial exoproducts such as lipopolysaccharides
and elastase induce harmful pathogenesis resulting in
tissue destruction.
Flagellins in P. aeruginosa perform several functions
during host infection [4]. Apart from enabling motility,
the flagellum of P. aeruginosa plays an indirect role in
membrane permeabilization and surfactant protein-me-
diated bacterial clearance [5]. Similarly, pili is involved
during inflammation due to glycosylation in the interface
between pili and host cells. Flagellins are classified into
two types: Type-a (polymorphic glycosylated) and type-b
2. Pathogenesis and Colonization
Pili, flagella, exoenzyme S, and mucoid exopolysaccha-
ride are recognized as major adhesins in P. aeruginosa.
Invading pathogens are recognized by Toll-like receptors
(TLRs) on epithelial cells and innate immunocytes, both
of which are then activated to express inflammatory me-
diators. Thereafter, defense systems such as mucociliary
clearance, phagocytosis and humoral immunity are pro-
moted to neutralize the danger [3].
Invading organisms are first trapped by the mucus
layer coating the airway epithelial cells. Airway mucin,
the main component of mucus, is a large heterogeneous
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Overview of Multidrug-Resistant Pseudomonas aeruginosa and Novel Therapeutic Approaches
glycoprotein with carbohydrate side chains consisting of
N-acetylglucosamine (GlcNAc), GalNAc, D-mannose,
L-fucose, and N-acetylneuraminic acid (NeuAc) which
may promote colonization, whereas binding to the gly-
colipids may cause an inflammatory response [6 ]. These
exposed oligosaccharide residues become adhesive re-
ceptors for P. aeruginosa and others microbes.
The diversity of oligosaccharide side chains on glycol-
proteins or glycolipids in mucin may determine which
organisms will effectively bind to it [7]. P. aeruginosa
has a variety of lectin-like adhesions (Figure 1), include-
ing pili, mucoid exopolysaccharide, and non-pilus ad-
hesins, represented by exoenzyme S, that have binding
domains similar to that of the pilus. Flagella motility and
pili, which mediate twitching motility in P. aeruginosa,
are thought to be the prevailing adhesins for the initial
attachment required for colonization of the airway tract
Alginate expression is observed afterward the initial
attachment of P. aeruginosa to a solid surface. Alginate
may be involved in cementing the primary adherence of
the non-pilus adhesion found on the surface of P.
aeruginosa so it can bind to respiratory cells or mucin in
the absence of other adhesions [3]. When the organisms
trapped in mucus multiply faster than the removal rate
the production of exoproducts increases, most of which
are virulent and result in decreased mucociliary transport
and airway epithelial cell function. The latter results in
enhanced mucus inactivity and cell surface colonization.
Following, quorum sensing and biofilm formation start.
Intracellular communication is involved in P. aeruginosa
biofilm development [8]. The phenomenon of quorum
sensing or cell-to-cell communication requires self-gen-
erated signal molecules, named autoinducers. As cell
density increases, there is a proportional increase in
autoinducer production. P. aeruginosa has at least two
quorum-sensing systems. Each system includes a gene
encoding a transcriptional activator, LasR or RhlR and a
gene encoding an autoinducer lasI or rhlI. These systems
contribute to the development of the biofilm. In addition,
Figure 1. Schematic interactions of the possible roles of P.
aeruginosa lectins during host recognition and biofilm for-
mation [10].
the LasR-las I and RhlR-rhlI quorum-sensing systems
regulate the expression of various virulence genes in a
density-dependent fashion [3].
In animal models of acute and chronic infections with
P. aeruginosa containing a mutation in quorum-sensing
genes, less tissue destruction was induced and less mor-
tality was observed compared with findings in wild-type
strains [9]. Bacteria inside a mature biofilm exhibit in-
creased resistance to antibacterials and phagocytic cells,
and are less stimulatory to the mucosa; these facts are
found in bacterial colonization grown particularly in in-
appropriate environments. It can be said that one of the
ways the pathogen and host coexist is established at the
site of colonization.
In a chronic colonization with P. aeruginosa biofilms,
the lungs show chronic inflammation that is associated
with the development of lymphocyte follicles around
respiratory bronchioles and with the influx of PMNs into
airway lumens [3].
3. General Mechanisms against Multiple
3.1. Multidrug Resistance
P. aeruginosa is naturally resistant to a significant num-
ber of antimicrobials (Table 1). Furthermore, they easily
acquire resistance to new antibacterial agents by muta-
tional changes or acquisition of genetic material. In a
study, P. aeruginosa strains isolated presented resistance
to carbenicillin and gentamicin. P. aeruginosa is intrin-
sically less susceptible to the fluoroquinolones and usu-
ally it is moderately susceptible or resistant [11].
Resistance of P. aeruginosa to commonly used thera-
peutic agents has increased in recent years. MDR can be
defined as resistance to at least four classes of antibiotics
used during treatment of these infections: third-genera-
tion cephalosporins, fluoroquinolones, aminoglycosides,
and carbapenems [12].
Emergence of MDR strains is often due to selective
pressure of antimicrobial therapy. Genetic studies con-
firm the selection of resistant mutants and their subse-
quent spread. Outbreaks caused by MDR P. aeruginosa
Table 1. Natural resistance of P. aeruginosa to antibiotics
Bacteria Natural resistance
P. aeruginosa
first-generation cephalosporins
nalidixic acid
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Overview of Multidrug-Resistant Pseudomonas aeruginosa and Novel Therapeutic Approaches
Copyright © 2012 SciRes. JBNB
may follow an increased use of third-generation cepha-
losporins or carbapenems for therapy of infections caused
by other resistant bacteria [2].
All bacteria rely on a heavily cross-linked peptidogly-
can layer for cell shape and morphological stability [13].
The formation of this layer depends on the catalytic ac-
tivity of transpeptidase enzymes, which utilize an active
site serine and perform their catalytic cycle by way of an
acylation/deacylation pathway. Beta-lactam antibiotics
inhibit the action of transpeptidases, effectively blocking
the transpeptidation reaction and therefore leaving bacte-
ria susceptible to cell lysis. Beta-lactamases confer sig-
nicant antibiotic resistance to their bacterial hosts by
hydrolysis of the amide bond of the four-membered beta-
lactam ring. Their mechanism depends heavily on the
concentration of zinc ions, required by the four different
classes of beta-lactamases during hydrolisis [14].
Bacteria exhibit two control mechanisms when in pre-
sence of metallic compounds: One based on sensing of
the environment and, in proportion to what is detected,
one of regulatory response [15].
The process occurs in the context of chemical gradi-
ents, which activate several metabolic pathways acquired
by bacteria along their evolutionary history. Enthalpy
plays a determinant role in this case: All non-deleterious
mutations attempt to minimize metabolic costs. Toxicity
of metals in the cellular medium can be either independ-
ent of concentration or regulated by it, in which case
metals at appropriate concentration levels become cata-
lytics. In the case of P. aeruginosa zinc is not only re-
quired for metabolic functions but fulfills a definitive
role in resistance to beta-lactams, also dependent on
chemical gradients. A similar case occurs with iron ac-
quisition, allowing the pathogen to degrade host iron
binding proteins and act as an extracellular protein,
bringing the host cell into metabolic stress [16].
Apart from the two general mechanisms described
above, the complexity in the genome of P. aeruginosa
provides precise binding mechanisms in different ways.
As in the case of beta-lactamases which hydrolize beta-
lactams by attacking their moieties, microcalorimetry
studies have shown that paralogous genes in P. putida
have the capacity to bind in different ways depending on
subtle changes in enthalpy [17]. Evidence suggests that
selective pressure induced by both natural and clinical
factors has forced adaptations based on both general
mechanisms (extracellular and within the cell) for mo-
lecular recognition as well as specific binding strategies
for novel antimicrobials based on physicochemical pa-
3.2. Efflux Pumps
The resistance of MDR strains may be mediated by the
active export of the antibiotics out of the bacterial cell
by efflux pumps [18]. Evidence from diverse bacterial
genomes indicates that approximately 5% - 10% of
genes are involved in transport, with a large proportion
of them encoding efflux pumps [19]. These can be or-
ganized into five superfamilies: small multidrug resis-
tance (SMR), multidrug endosomal transporter (MET),
major facilitator superfamily (MFS), resistance nodula-
tion division (RND) and multi antimicrobial resistance
(MAR) [20]. The latter indicates the mechanism has
evolved long ago and is shared amongst all Gram-posi-
tive and Gramnegative bacteria. P. aeruginosa exhibits
several efflux pump systems that allow it to be resistant
to several antimicrobial agents [21]. Tab le 2 summarizes
some of these systems and their effect on resistance to
different agents.
3.3. Other Resistance Mechanisms
Another mechanism present in P. aeruginosa is the for-
mation of permeability barriers (OM) [18]. Impaired
penetration of different substances through the mem-
brane (e.g. imipenem) is due to diminished expression of
specific OM protein. It has been shown that OM perme-
abilizers such as EDTA increase susceptibility to antibi-
otics, indicating that the lack of OprD protein leads to a
reduction of active antibiotic molecules capable of reach-
ing the target penicillin-binding-proteins.
Two-component systems (2CS) are common molecu-
lar mechanisms that allow diverse bacteria to have adap-
tive regulation in response to complex environments,
often composed by a sensor histidine kinase and a re-
sponse regulator [22]. The sensor kinase is composed of
Table 2. Efflux pump systems associated to antibiotics resistance in P. aeruginosa [21].
Efflux pump system Antimicrobial agents
MexAB-OprM fluoroquinolones, beta-lactams, tetracyclines, macrolides, chloramphenicol,
novobiocin, trimethoprim, sulphonamides
MexEF-OprN fluoroquinolones, chloramphenicol, trimethoprim, imipenem
MexXY-OprM fluoroquinolones, aminoglycosides, tetracyclines, erythromycin
MFP-RND-OMF multidrug efflux
pump systems fluoroquinolones, tetracyclines
Overview of Multidrug-Resistant Pseudomonas aeruginosa and Novel Therapeutic Approaches
at least one signal recognition domain coupled to an
autokinase domain in an input-transmitter arrangement.
Two hypothesis exist regarding the evolution of 2CS.
The co-evolution model proposes that 2CS genes have
appeared as a result of duplication and further different-
tiation of these in bacterial genomes. The recruitment
model on the other hand proposes that some of the 2CS
operons have appeared as a result of an assembly of a
sensor gene and a regulator gene from heterologous 2CS
genes. Both are supported by evidence from phylogenetic
analysis and gene regulatory network modeling in the P.
aeruginosa PA01 strain.
Finally, it has been shown that cytotoxicty is an im-
portant mechanism that contributes to high morbidity and
mortality in P. aeruginosa infections, particularly in cys-
tic fibrosis [23]. Along with mucoidy resultant from the
release of alginate, P. aeruginosa synthesizes a secretory
apparatus (Type III) that allows it to inject toxins from
their cytoplasm into the target cell. The latter mechanism
allows mucoid bacteria to lyse the host’s macrophages
and overcome various defense such as in the case of cys-
tic fibrosis lung infection.
3.4. Genomic Profile of P. aeruginosa
Complete sequencing of the P. aeruginosa PA01 strain
(Figure 2) revealed a complex organism, comparable in
terms of genome length (6.3 Mb) and amount of open
reading frames (5570 ORFs) to Saccharomyces cere-
visiae [24]. Comparison with E. coli revealed a strong
evolutionary link between both. This fact is based on
evidence of almost one half of the ORFs in P. aeruginosa
having an E value of 10e5 in BLASTP alignments with
E. coli segments despite only 40% of amino-acid identity
in the common coding regions. Also, low gene replica-
tion across the genome indicates that such a compara-
tively large genome has vast potential of functional di-
versity, which may support rich mechanisms responsible
for multidrug resistance thanks to environmental versatil-
ity. Available genome data supports the hypothesis of the
existence of evolutionary paths where resistance to natu-
rally available antibiotics was acquired.
The wide collection of genes in P. aeruginosa can be
mapped to diverse functions. Table 3 shows some rele-
vant data regarding the relation between the gene pool
and mechanisms ranging from cell regulation to chemo-
sensing and chemotaxing. It is interesting to note that the
limited ability to grow on sugars has forced P. aerugi-
nosa down to an evolutionary path where it adapted to
Figure 2. Circular representation of the P. aeruginosa PA01
genome [24].
Table 3. Number of genes associated to functions related to multidrug resistance in P. aeruginosa [24].
Function No. of genes Cellular act i v it ies and pro d u c ts
Cell regulation 521 Transcriptional regulators, two-component regulatory system proteins
Cell-surface exposure 71 OprD family of specific porins, TonB family of gated porins (metal-related uptake), OprM family
of outer membrane proteins (efflux and secretion)
Import of nutrients 555 300 cytoplasmic membrane transport systems
Metabolism 626
Amino acid biosynthesis and metabolism, carbon compound catabolism, central intermediary
metabolism, energy metabolism, fatty acid and phospholipid metabolism, nucleotide biosynthesis
and metabolism
Intrinsic drug resistance and
efflux systems 34 Resistance/nodulation/cell division, major facilitator superfamily, small multidrug resistance
family, multidrug and toxic compound extrusion family, ATP-binding cassette family
Protein secretion 83 Secretion of alkaline protease, general secretion pathway, contact-dependent delivery of proteins
into the cytoplasm of host cells, exoenzymes S, T and Y
Chemotaxis 43
Flagella-mediated swimming towards chemoattractors, attraction to sugars, amino acids and
inorganic phosphate, repulsion to thiocyanic and isothiacyanic esters
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Overview of Multidrug-Resistant Pseudomonas aeruginosa and Novel Therapeutic Approaches 523
use an ample range of carbon compounds.
Recent advances in in silico genomic approaches have
provided an opportunity to specifically highlight poten-
tial drug targets and has facilitated a paradigm shift from
direct antimicrobial screening programs toward rational
target-based strategies, where drug discovery starts at the
level of the gene [25].
According to the generally used definition, essential
genes cannot be deleted from an organism without a le-
thal effect, being more evolutionarily conserved than
nonessential genes. If genes are grouped by their func-
tional classification, variation is lowest for genes in-
volved in transcription, RNA processing, degradation,
translation, post-translational modification, degradation
and cell division, which are enriched for essential genes
(Figure 3). In addition to gene essentiality, a high gene
expression rate has previously been shown to correlate
with low sequence variation, and it was proposed that the
underlying driving force for the slower evolution of es-
sential genes is that most of the highly expressed genes
are also indispensable in general [25].
4. Current Approaches against Multidrug
4.1. New Strategies with Known Antimicrobials
Polymyxin B agents were used in the therapy of infec-
tions in the 1970s, but due to reported toxicity and the
subsequent development of less toxic drugs such as
nephrotoxicity, ototoxicity and neuromuscular blockade,
their use has been discontinued. Polymyxin B is a poly-
peptide antibiotic produced by a strain of Bacillus po-
lymyxa and is primarily used for resistant Gram-negative
infections. Now, with the emergence of MDR strains,
their clinical use is being reconsidered [2]. Several re-
ports in the past five years showed that colistin toxicity is
not as frequent as previously reported [26]. Renal failure
was rare and usually reversible, while neurotoxicity was
not reported.
Furthermore, colistin (polymyxin E) has been used in
several cases as a salvage agent during therapy of infec-
tions caused by strains resistant to all available antim-
icrobials [26]. However, clinical strains with reduced
susceptibility to polymyxin B have been reported [27].
Colistin, in combination with antibiotics from other
classes, may be a useful agent for the treatment of infec-
tions caused by pandrug-resistant P. aeruginosa [28].
Aztreonam may be used in the therapy of infections
caused by P. aeruginosa. Combination therapy of az-
treonam with other antimicrobials may be effective. A
two-drug (aztreonam and amikacin) and a three-drug com-
bination (aztreonam, ceftazidime, and amikacin) were
very active against MDR strains of P. aeruginosa in an in
vitro study [29].
Imipenem and meropenem are carbapenems com-
monly used in hospital practice. Many reports confirm
their usefulness in the therapy of nosocomial infections
caused by MDR Gram-negative bacilli. Apart from
imipenem and meropenem, new carbapenems are being
evaluated for their efficacy against MDR pathogens [2].
Carbapenems may be administered as monotherapy, but
with the emergence of MDR P. aeruginosa, combination
Figure 3. Protein evolution rates in genes of different functional categories [25].
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Overview of Multidrug-Resistant Pseudomonas aeruginosa and Novel Therapeutic Approaches
therapies are being evaluated.
4.2. Novel Antimicrobials
Efflux pump inhibitors are under development for use in
therapy of infections with resistant strains. In P. aerugi-
nosa, two enzymes are involved: the enoyl-acyl carrier
protein (ACP) reductase FabI and the alternative enoyl-
ACP reductase FabK. Triclosan and other novel FabI-
and FabK-directed inhibitors could prove to be broad-
spectrum antibacterial agents, particularly for the therapy
of infections caused by MDR pathogens [30].
Bacteriophage therapy of bacterial infections has also
been investigated for many years. It has now received
renewed attention as a result of the emergence of MDR
strains of pathogenic bacteria. Several studies have
shown the efficacy of bacteriophages in the treatment of
experimental infections caused by P. aeruginosa in ani-
mals [31]. These studies indicate bacteriophages might
also be useful in the therapy of infections caused by
MDR bacterial strains in humans. Bacteriophages may be
administered alone or in combination with antibiotics,
and can be given prophylactically or as a therapy of in-
fection. They offer several advantages, as they are very
specific, replicate at the site of infection, and no serious
adverse effects of their administration have been de-
scribed. However further studies are needed in order to
assess their therapeutic use in humans.
4.3. Nanomedicine
Use of nanotechnology in in the treatment of infections
consist in designing, delivering antimicrobial drugs, and
diagnosis and control of infections, in particular in over-
coming multidrug-resistant microorganisms, has been
explored as a good alternative to the current antibiotics.
The recent development of nanotechnology has al-
lowed the study of the effect of nanostructures in the
biomedical area, and has promoted studies around the use
of nanomaterials and nanoparticles as antimicrobial
agents. Nanomaterials can be useful for in vivo and in
vitro biomedical research and applications. The integra-
tion of nanomaterials with biology has led to the devel-
opment of diagnostic devices, contrast agents, analytical
tools, physical therapy applications, molecular sensors
and drug delivery vehicles. From all nanomaterials with
antibacterial properties, metallic nanoparticles provide
the best results.
The importance of studying and developing bacteri-
cidal nanomaterials is given by the increase of new bac-
teria strains resistant against most potent antibiotics
available and antimicrobial nanoparticles board multiple
biological pathways (Figure 4), found in broad species
of microbes and many concurrent mutations would have
to occur in order to develop resistance against nanopart-
ciles antimicrobial activities [28].
The latter has promoted research in the well-known
activity of silver ions and silver-based compounds, in-
cluding silver nanoparticles. Their effect was shown to
be size and dose dependent, and was more pronounced
against gram-negative bacteria than gram-positive or-
ganisms [32].
Silver nanoparticles (AgNP) are intrinsically anti-
bacterial, whereas gold nanoparticles (AuNP) have an-
timicrobial effect only when ampicillin was bound to
their surface. Both AuNP and AgNP functionalized with
ampicillin are bactericides against Gram-negative and
Figure 4. Various antimicrobial mechanisms of nanomaterials [28].
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Overview of Multidrug-Resistant Pseudomonas aeruginosa and Novel Therapeutic Approaches 525
Gram-positive bacteria. Most importantly, when AuNP
and AgNP are functionalized with ampicillin they be-
came potent bactericidal agents with unique properties
that subverted antibiotic resistance mechanisms of multi-
ple-drug-resistant bacteria as P. aeruginosa [33].
Currently nanoparticles such as chitosan nanoparticles,
quantum dots, dendrimers and liposomes are under study
as antimicrobial agents. Polymyxin B-loaded liposomes
represent a successful example of liposomal antimicro-
bial drug delivery [34]. As mentioned before, polymyxin
B has been recognized as a viable treatment for P.
aeruginosa related infections. However, its systemic use
has been limited due to toxic side effects. It has been re-
ported that liposomal encapsulation of polymyxin B dra-
matically diminishes side effects and improves its antim-
icrobial activity against resistant strains of P. aeruginosa
[35]. The action mechanism of liposomal polymyxin B
against bacteria has been identified as membrane fusion.
Membrane fusion between liposomes and bacteria is a
rapid and spontaneous process driven by non-covalent
forces such as van der Waals force and hydrophobic in-
teractions that minimize the free energy within the sys-
tem. Antibiotic efflux is a widely accepted mechanism of
microbial drug resistance, in which proteinaceous trans-
ports located in bacterial membranes preferentially pump
antimicrobial drugs out of the cells. When liposomes fuse
with cell membranes, a high dosage of drug contents is
immediately delivered to the bacteria, potentially sup-
pressing the antimicrobial resistance of the bacteria by
overwhelming the efflux pumps, thereby improving drug’s
antimicrobial activity [34].
5. Concluding Remarks
The pathogenesis of chronic airway infection of P.
aeruginosa has been discussed, and the factors affecting
the progress of the pathogenic manifestations described
in detail. This review focuses at first on bacterial adher-
ence, biofilm formation, immunological disorders and
current and novel therapeutic treatment.
Resistance to antibiotics exhibited by some strains of
pathogenic bacteria pose a serious challenge in combat-
ing infectious diseases. As it is known, application of
more powerful antibiotics can lead to limited and tempo-
rary advances and eventually contribute to developing
greater resistance. Resources against multidrug-resistant
pathogenic infections are now limited.
Due to their promising antimicrobial properties, nano-
materials and nanoparticles are currently being studied as
potential, highly potent antimicrobial agents for a variety of
medical applications. Different kinds of nanoparticles have
been investigated for carrying and delivering anti-biotics.
Also, nanoparticles enable combining multiple approaches
in order to enhance antimicrobial activity and overcome the
various resistance mechanisms in P. aeruginosa.
Further investigation is required indeed. In particular,
the performance of nanomaterials and nanoparticles is an
interdisciplinary endeavor. Tools from pathology, im-
munology, biocompatible materials, polymers, nanotoxi-
cology, pharmacology and nanotechnology are essential
for such task.
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