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Current Pharmaceutical Design, 2013, 19, 209-222 209

Mechanisms of
-lactam Resistance Among Pseudomonas aeruginosa

Daniel J. Wolter1 and Philip D. Lister2,*

1
Department of Pediatrics, University of Washington, Seattle, WA; 2Department of Medical Microbiology and Immunology, Creigh-
ton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA

Abstract: Treatment of serious P. aeruginosa infections becomes more challenging with each passing year. As this pathogen acquires
more transferrable resistance mechanisms and continues to rapidly adapt and emerge resistant during the course of antimicrobial therapy,
we face the growing threat of pan-resistance. This review has focused on those mechanisms that directly impact the future of
-lactam
antibiotics, including the production of
-lactamases, porin-mediated resistance, and/or the overexpression of RND efflux pumps. With
the pipeline of new anti-pseudomonal agents diminishing, it is essential that novel therapeutic strategies be explored. These include tar-
geting biofilm formation and maintenance, virulence factors, and resistance mechanisms. Furthermore, we must continue to search for ef-
fective antibacterial combinations to not only prevent further emergence of resistance but also treat resistant strains already in the envi-
ronment.

Keywords: Pseudomonas aeruginosa,
-lactam, resistance.

INTRODUCTION For the subsets of nosocomial pneumonia, health-care associated

Antibacterial resistance is an increasing threat to the treatment
of gram-positive and gram-negative pathogens. Among the gram-
negatives, P. aeruginosa has historically been one of our most dif-
ficult therapeutic challenges. This pathogen is not only armed with
an impressive arsenal of chromosomally-encoded resistance
mechanisms, but has the propensity to acquire a wide range of re-
sistance genes from its environment.
The focus of this review will be on the diversity of resistance
mechanisms that threaten the clinical use of
-lactams for P. aeru-
ginosa infections, including
-lactamases, porin-mediated resis-
tance, and efflux-mediated resistance. For some of these mecha-
nisms, P. aeruginosa has the ability to alter production and/or activ-
ity and emerge resistant during the course of treating a patient. Fur-
thermore, with the cooperative effects of multiple mechanisms, the
threat of pan-
-lactam resistant P. aeruginosa is a growing concern.
CLINICAL SIGNIFICANCE AND THERAPEUTIC CHAL-
LENGE OF PSEUDOMONAS AERUGINOSA
P. aeruginosa is a ubiquitous microbial pathogen that can be
isolated from a wide variety of environmental sources including
plants, animals, and humans. As a nosocomial threat, P. aeruginosa
has been isolated from respiratory therapy equipment, antiseptics,
sinks, medicines, and hydrotherapy pools [1]. Community reser-
voirs include swimming pools, humidifiers, hot tubs, and contact
lens solution [2-4]. Although P. aeruginosa is not normally a part
of the normal flora, a significant proportion of hospitalized patients
can become colonized [1], especially if protective barriers of skin or
mucous membranes have been breached or if the patient is im-
munocompromised [3, 5] Patient populations at particular risk are
those on mechanical ventilators, patients with catheters, surgical
patients, patients with severe burn wounds, and seriously ill patients
in the intensive care unit [6-12]. In addition, patients for whom the
normal protective flora has been disrupted by antimicrobial therapy
are also at increased risk for colonization [6, 13, 14].
Although P. aeruginosa can cause community-acquired infec-
tions, the majority of serious infections are nosocomial. According
to the CDC National Nosocomial Infections Surveillance System
(NNISS), P. aeruginosa ranks fifth among nosocomial pathogens
for overall frequency of isolation in U.S. hospitals [15, 16].
*Address correspondence to this author at the Department of Medical Mi-
crobiology and Immunology, Creighton University School of Medicine,
USA; Tel: 402-280-1224; E-mail: plister@cnm.edu
pneumonia, and ventilator associated pneumonia, P. aeruginosa is
the second most common pathogen identified [17, 18]. In addition,
P. aeruginosa is a leading cause of infections among patients in the
intensive care unit [11, 12].
Selection of appropriate antibacterial therapy is essential to
optimizing the treatment of serious infections with P. aeruginosa
[19, 20]. The initial challenge with P. aeruginosa centers on its
intrinsic antibiotic resistance that is not observed in most other
gram-negative bacilli. This inherent resistance is due to low perme-
ability of its outer membrane [21] and intrinsic basal expression of
chromosomal resistance mechanisms [22]. Complicating selection
of appropriate therapy is the propensity for P. aeruginosa to de-
velop resistance to multiple classes of antibacterial agents. Multi-
drug resistant strains are isolated with alarming frequency, and
these strains develop a multi-drug resistant phenotype through the
acquisition of resistance genes on mobile genetic elements and/or
through mutational events influencing the expression and/or activity
of chromosomal resistance mechanisms [22]. An even greater con-
cern is the propensity for P. aeruginosa to emerge resistant during
the course of therapy, leading to clinical failure and potentially
doubling the length of hospital stay and the cost of patient care [23].
This review will focus specifically on mechanisms of
-lactam
resistance among P. aeruginosa. Figure 1 summarizes the general
mechanisms by which P. aeruginosa expresses resistance to this
antibacterial class.
-lactam antibiotics enter the periplasmic space
of P. aeruginosa by direct penetration across the outer membrane or
through porins located in the outer membrane (Fig. 1A). Once in
the periplasmic space,
-lactams exert their antibacterial effect by
binding to and inactivating the penicillin-binding proteins involved
in cell wall biosynthesis. Although mutational changes impacting
the affinity of penicillin-binding proteins for
-lactams may play a
role in resistance for some strains, the primary mechanisms of
-
lactam resistance are 1) production of an inactivating enzyme (
-
lactamase), 2) porin-mediated resistance, and 3) efflux-pump medi-
ated resistance (Fig. 1B).

-LACTAMASES OF Pseudomonas aeruginosa
The production of drug-inactivating enzymes is the most com-
mon mechanism of
-lactam resistance among gram-negative bac-
teria. Molecular and genetic analyses of clinical isolates have
shown that P. aeruginosa can produce a diversity of
-lactamases,
some of which are encoded by chromosomal genes and others on
mobile genetic elements. Although the
-lactamases produced by P.

1873-4286/13 $58.00+.00 © 2013 Bentham Science Publishers

210 Current Pharmaceutical Design, 2013, Vol. 19, No. 2 Wolter and Lister

A.

O O O

OM

PG

PS
PBP PBP PBP PBP

CM

B.

O O O

X OM

PG

O PS
O
PBP PBP PBP

CM

Fig. (1). Mechanisms of
-lactam Resistance Among P. aeruginosa. Panel A: Interactions of
-lactams with “wild-type” susceptible P. aeruginosa.
-
lactam molecules penetrate into the periplasmic space either by passing directly through the outer membrane or entering through specific porins, e.g. OprD for
carbapenems ( ). Once they enter the periplasmic space,
-lactams can interact with their target penicillin binding proteins (PBP) located on the outside of
the cytoplasmic membrane. Panel B: Mechanisms of resistance to
-lactams. The primary mechanisms of
-lactam resistance include the production of
-

lactamases ( ), decrease or loss of OprD porin in the outer membrane, and overproduction of RND efflux pumps ( )

aeruginosa can vary with respect to their spectra and efficiency of
hydrolysis, these characteristics alone do not define the resistance
profiles associated with different enzymes. Instead,
-lactamase-
associated resistance in P. aeruginosa is also dependent upon the
efficiency of drug penetration, ability of this pathogen to minimize
drug accumulation in the periplasmic space (porin-mediated resis-
tance and/or extrusion by efflux pumps), and the cooperative effects
of different
-lactamases within the same cell. Therefore, it is not
surprising that the resistance profile associated with a
-lactamase
in one strain of P. aeruginosa may differ from the resistance profile
associated with that same
-lactamase in a different strain. With
this in mind, the following sections will summarize the different
families of
-lactamases that have been detected in clinical isolates
of P. aeruginosa and the general resistance threat they provide
when produced by this pathogen. The
-lactamases have been cate-
gorized based on the recently updated classification of Bush and
Jacoby [24], and are summarized in Table 1.
Group 1 Chromosomal AmpC Cephalosporinase. AmpC is a
serine-based
-lactamase belonging to molecular class C and is
characterized by its more efficient hydrolysis of cephalosporins
than penicillin and its relative resistance to inactivation by clavu-
lanate and tazobactam [24]. The AmpC of P. aeruginosa is natu-
rally an inducible enzyme. In the absence of an inducing
-lactam,
wild-type strains of P. aeruginosa produce low basal levels of
AmpC and may be susceptible to the anti-pseudomonal penicillins,
penicillin-inhibitor combinations, cephalosporins and carbapenems
if no other resistance mechanisms are operative [25]. However, the
increased production of AmpC in P. aeruginosa can cause resis-
tance to virtually all
-lactams, except to the carbapenems [22, 26].
Although data have suggested that AmpC plays a role in the intrin-
sic level of susceptibility of P. aeruginosa to carbapenems [27-30],
overproduction of AmpC does not significantly decrease P. aerugi-
nosa susceptibility to carbapenems [27, 30-33]. Resistance to the
carbapenems usually requires the cooperation of additional resis-
tance mechanisms, e.g. efflux pump overproduction, outer mem-
brane porin decrease, and/or co-production of additional carbap-
enem-hydrolyzing enzymes [22].
One pathway to overproduction of AmpC is through the re-
versible induction of ampC expression during exposure with certain

-lactams (cephamycins and carbapenems) and the
-lactamase
Antibacterial Resistant Pseudomonas aeruginosa Current Pharmaceutical Design, 2013, Vol. 19, No. 2 211

Table 1.
-lactamases of P. aeruginosa

Functional Group Molecular Class Potential Resistance Impact Representative Enzymes

Group 1 C Penicillins Chromosomal AmpC Cephalosporinase

Penicillin-Inhibitor Combinations
Cephalosporins
Cephamycins
Monobactams

Group 1e C Penicillins Extended-Spectrum AmpC Cephalosporinase

Penicillin-Inhibitor Combinations
Cephalosporins
Cephamycins
Monobactams
Carbapenems

Group 2b A Penicillins TEM-1, TEM-2, SHV-1

Early cephalosporins

Group 2be A Penicillins TEM-4, TEM-21, TEM-24, TEM-42, TEM-116

Early cephalosporins
Extended-spectrum cephalosporins SHV-2, SHV-2ª, SHV-5, SHV-12
Monobactams
CTX-M-1, CTX-M-2, CTX-M-43

PER-1, PER-2

VEB-1, VEB-1a, VEB-1b, VEB-2

GES-1, GES-8, GES-9

BEL-1, BEL-2

Group 2c A Penicillins PSE-1, PSE-3, PSE-4, PSE-5

Ticarcillin-clavulanate
CARB-3, CARB-4

Group 2d D Penicillins OXA-1, OXA-2, OXA-3, OXA-4, OXA-5, OXA-

Penicillin-Inhibitor Combinations 6, OXA-10, OXA-13, OXA-20, OXA-46, OXA-
50, OXA-56,

LCR-1

Group 2de D Penicillins OXA-11, OXA-14 to OXA-19, OXA-28, OXA-31,

Penicillin-Inhibitor Combinations OXA-32, OXA-35, OXA-45, OXA-74, OXA-147,
OXA-161
Cephalosporins
Monobactams

Group 2df D Penicillins OXA-40, OXA-50-type

Penicillin-Inhibitor Combinations
Narrow-spectrum Cephalosporins
Carbapenems
212 Current Pharmaceutical Design, 2013, Vol. 19, No. 2
(Table 1) Contd....
Functional Group Molecular Class Potential Resistance Impact
Group 2f A Penicillins
Penicillin-Inhibitor Combinations
Cephalosporins
Carbapenems
Group 3 B Penicillins
Penicillin-inhibitor combinations
Cephalosporins
Cephamycins
Carbapenems
inhibitor clavulanate [34-38]. Although several components of the
ampC regulatory system have been identified and characterized, the
precise pathway of induction remains unclear [22]. Induction of
ampC expression provides P. aeruginosa with resistance to ce-
foxitin, but alone does not provide resistance to the carbapenems.
The clinical significance of clavunate’s induction of ampC is com-
plex. Due to induction by clavulanate, Enterobacteriaceae that pro-
duce an inducible ampC are usually more susceptible to ticarcillin
than ticarcillin-clavulanate [39]. By contrast, MICs of ticarcillin-
clavulanate against P. aeruginosa remain similar to those of ticar-
cillin alone despite the induction of ampC [36]. The reason for this
discrepancy appears to relate to the concentration of clavulanate
used in CLSI-recommended susceptibility assays (2 μg/ml), a con-
centration which is too low to induce sufficient levels of AmpC that
would impact the potency of ticarcillin in the combination [36].
However, pharmacodynamic studies have demonstrated that the
level of induction achieved with pharmacokinetically-relevant con-
centrations of clavulanate is sufficient to negatively impact the
antibacterial activity of the combination [36].
A more serious therapeutic threat is when the regulation of
ampC is lost through derepression, defined as constitutive high-
level ampC expression. As a result, P. aeruginosa becomes resis-
tant to virtually all
-lactams. The pathway to derepression of
ampC usually involves genetic mutations that alter proteins respon-
sible for regulating ampC expression [22], and these mutational
events can lead to the emergence of resistance during therapy.
Emergence of resistance due to ampC derepression has been re-
ported in up to 56% of patients treated with anti-pseudomonal peni-
cillins, penicillin-inhibitor combinations, extended-spectrum cepha-
losporins, and aztreonam [40-48], and most commonly occurs dur-
ing treatment of infections outside the urinary tract and in patients
with cystic fibrosis and neutropenia.
Group 1e Extended-Spectrum AmpC Cephalosporinases. Over-
expression of ampC alone does not always impact susceptibility of
P. aeruginosa to the carbapenems. However, recently described
mutational variants of AmpC (extended-spectrum AmpC) have
been characterized that can directly influence carbapenem suscepti-
bility. These AmpC variants were first described in Enterobacte-
riaceae [49-53], and more recently among P. aeruginosa [54]. Al-
though these enzymes can exhibit increased hydrolytic activity
against cephalosporins and imipenem, overproduction of extended-
spectrum AmpCs seems to be a requirement for carbapenem resis-
tance [54]. Characterization of 32 carbapenem-intermediate and –
resistant P. aeruginosa isolates from France demonstrated that 21
Wolter and Lister
Representative Enzymes
KPC
GES-2, GES-5
IMP-1, IMP-2, IMP-4, IMP-6, IMP-7, IMP-9,
IMP-10, IMP-11, IMP-13, IMP-14, IMP-15, IMP-
16, IMP-18, IMP-22,
VIM-1 to VIM-11, VIM-13, VIM-15 to VIM-18,
SPM-1
GIM-1
(65%) overexpressed an extended-spectrum AmpC cepha-
losporinase [55].
Group 2b
-lactamases. Group 2b
-lactamases are serine-
based enzymes from molecular class A and include the common
plasmid-encoded enzymes TEM-1, TEM-2, and SHV-1 [24]. These

-lactamases were first found in members of the Enterobacteriaceae
[56, 57], and later identified in strains of P. aeruginosa [58]. Group
2b
-lactamases most readily hydrolyze the penicillins and the early
cephalosporin antibiotics.
Group 2be Extended-Spectrum
-lactamases. Group 2be in-
cludes a wide variety of serine-based extended-spectrum
-
lactamases (ESBLs) from molecular class A. The first ESBLs char-
acterized were variants of the Group 2b SHV-1, TEM-1, and TEM-
2
-lactamases and were discovered in members of the Enterobacte-
riaceae [59-61]. These ESBLs are able to hydrolyze the penicillins
and early cephalosporins like the Group 2b enzymes, but also dem-
onstrate an extension of their hydrolytic capabilities to include ex-
tended-spectrum oxyimino-cephalosporins (ceftazidime and cefo-
taxime), and the monobactam aztreonam [62, 63].
ESBLs have also been identified in P. aeruginosa. The first
TEM-derived ESBL reported in P. aeruginosa was TEM-42 from a
clinical isolate in France [64]. Since that first report, only four other
TEM-derived ESBLs have been described, including TEM-4, TEM-
21, TEM-24, and TEM-116 [65-68]. In addition, four SHV-derived
ESBLs (SHV-2, SHV-2a, SHV-5, and SHV-12) have been identi-
fied in clinical isolates of P. aeruginosa [69-72].
The CTX-M-family of
-lactamases represents a group of en-
zymes that are not closely related to either the TEM- or SHV-
derived ESBLs, but are classified as ESBLs based upon their hydro-
lytic profiles [73]. These enzymes share homology with the chro-
mosomal AmpC of Kluyvera ascorbata [74]. To date, three CTX-
M-family ESBLs have been identified in P. aeruginosa, and include
CTX-M-1, CTX-M-2, and CTX-M-43 [65, 75, 76].
Additional Group 2be ESBLs that show limited homology with
TEM- or SHV-derived ESBLs include the PER-type, VEB-type,
GES-type, BEL-type, and PME-1
-lactamases. PER-1 was first
described in 1993 in a strain of P. aeruginosa from France [77]. A
closely related enzyme, PER-2, has also been identified in P. aeru-
ginosa [75]. The first VEB-type ESBL found in P. aeruginosa was
VEB-1, also from a clinical isolate in France [78]. Subsequently,
three other VEB-like ESBLs (VEB-1a, VEB-1b, and VEB-2) have
been identified in P. aeruginosa and share > 99% amino acid se-
quence homology with VEB-1 [79, 80]. The GES-1 ESBL was
Antibacterial Resistant Pseudomonas aeruginosa
discovered in a strain of K. pneumoniae from French Guiana [81],
and then subsequently in P. aeruginosa [82]. Extended-spectrum
-
lactamases GES-8, GES-9, and GES-13 have also been identified in
isolates of P. aeruginosa [83-85]. The extended-spectrum
-
lactamase BEL-1 was discovered in 2005 in a clinical isolate of P.
aeruginosa from Belgium [86], and more recently, BEL-2 was
found in another P. aeruginosa isolate from Belgium [87]. The
most recent ESBL discovered, PME-1 (Pseudomonas aeruginosa
ESBL 1) was described in a clinical isolate of P. aeruginosa from
Pennsylvania and shares 50% amino acid identity with the L2
-
lactamase of Stenotrophomonas maltophilia [88].
Group 2c Penicillinases: The Group 2c enzymes encompass a
relatively small group of serine-based penicillinases from molecular
class A [24]. Group 2c enzymes identified in P. aeruginosa include
PSE-1, PSE-3, PSE-4, PSE-5, CARB-3, and CARB-4. Although
these enzymes are inhibited by clavulanate, they hydrolyze ticarcil-
lin with such efficiency that they can provide P. aeruginosa with
resistance to ticarcillin-clavulanate [89-91]. In contrast, strains of P.
aeruginosa that produce PSE-type enzymes are more susceptible to
piperacillin-tazobactam, most likely due to the decreased hydrolysis
of piperacillin allowing tazobactam to be a more effective inhibitor
[90].
Group 2d OXA-type Penicillinases: The Group 2d
-lactamases
are molecular class D enzymes class A enzymes with respect to the
active site serine, but they are only weakly inhibited by clavulanate
and tazobactam [24]. The characteristics and clinical importance of
these enzymes have been extensively reviewed by Poirel et al. [92].
Although these enzymes were first distinguished by the increased
hydrolytic activity against cloxacillin and oxacillin, thus the desig-
nation OXA-type
-lactamases, this phenotype does not define all
enzymes in the family [92]. The OXA-family of enzymes repre-
sents one of the largest and most diverse groups of
-lactamases,
ranking second behind the TEM-family of enzymes [24]. Although
different OXA-type enzymes have been isolated from a variety of
gram-negative bacterial species [92], many of the OXA-type
-
lactamase variants can be found in isolates of Acinetobacter
baumannii and P. aeruginosa [92]. Table 1 includes representative
Group 2d OXA-type
-lactamases detected in P. aeruginosa. Due
to their limited hydrolytic profiles and lack of inhibition by ta-
zobactam and clavulanate, the Group 2d OXA-type
-lactamases
primarily provide P. aeruginosa resistance to the anti-pseudomonal
penicillins and inhibitor-penicillin combinations [92].
Group 2de OXA-type Extended-Spectrum
-lactamases: The
first published extended-spectrum OXA-type
-lactamase was
OXA-11 [93]. This enzyme is a variant of the narrow-spectrum
OXA-10 (formerly PSE-2) and was first identified in 1991 in a P.
aeruginosa isolate from Turkey [93]. Over the past two decades,
several other extended-spectrum OXA-family enzymes have been
identified, primarily among clinical isolates of P. aeruginosa [92,
94] (Table 1). Although the hydrolytic profiles can vary substan-
tially, the OXA-type ESBLs are characterized by their increased
hydrolysis of the oxyimino-cephalosporins and aztreonam and can
provide resistance to these drugs [92].
Group 2df OXA-type Carbapenemases: The carbapenem-
hydrolyzing OXA-type
-lactamases have been identified most
frequently among isolates of A. baumannii, and most are encoded
by chromosomal genes [95]. To date, only a few OXA-type carbap-
enemases have been reported in P. aeruginosa (Table 1) [96, 97].
The OXA-40 carbapenemase described in P. aeruginosa was shown
to be identical to the enzyme found in A. baumannii [97]. Although
the blaOXA-40 gene is found on similar plasmids in both P. aerugi-
nosa and A. baumannii [97], it was originally described as a chro-
mosomal gene in A. baumannii [98]. P. aeruginosa also encodes for
a chromosomal OXA-50 enzyme, of which sequence variants have
been described and characterized as carbapenemases [96]. Although
the OXA-type carbapenemases have a high affinity for carbap-
Current Pharmaceutical Design, 2013, Vol. 19, No. 2 213
enems, they do not efficiently hydrolyze these substrates and their
clinical significance is difficult to evaluate [95, 99].
Group 2f Carbapenemases: The Group 2f carbapenemases are
serine-based
-lactamases belonging to molecular class A [24,
100]. In addition to the carbapenems, these
-lactamases are capa-
ble of hydrolyzing the penicillins, cephalosporins, and aztreonam,
but they are inhibited by tazobactam and clavulanic acid [24, 99].
Although some Group 2f enzymes are encoded by chromosomal
genes (e.g. SME), the class A carbapenemases of clinical impor-
tance to P. aeruginosa are carried on plasmids.
The first family includes the GES
-lactamases, of which GES-
1 was discovered as an ESBL in an isolate of K. pneumonia [81].
Two variants, GES-2 and GES-5, have been identified among P.
aeruginosa clinical isolates and nosocomial outbreaks from differ-
ent geographic regions [101-105]. Although they were first consid-
ered ESBLs based on their hydrolytic profiles, these enzymes dem-
onstrate an extension of their hydrolytic activity to include
imipenem [99, 100, 104].
The second family includes the Klebsiella pneumoniae carbap-
enemases (KPCs), which were discovered in and most commonly
found among clinical isolates of K. pneumonia and other members
of the Enterobacteriaceae [99, 100]. Currently, 12 different variants
of KPCs (KPC-2 through KPC-13) have been identified. The first
KPC-producing P. aeruginosa were reported among clinical iso-
lates in Colombia, and these isolates produced KPC-2 [106]. Sub-
sequently, KPC-2 has been identified among isolates of P. aerugi-
nosa from Puerto Rico [107], Trinidad and Tobago [108], China
[109], and the United States [110], and KPC-5 was characterized in
a clinical isolate of P. aeruginosa from Puerto Rico [111]. Strains
of P. aeruginosa that produce KPCs can exhibit resistance to all
-
lactam antibiotics.
Group 3 Metallo-
-lactamases: The Group 3 metallo-
-
lactamases are molecular class B enzymes that are characterized by
their requirement for a zinc ion in the active site [24, 112]. As a
result of their broad-spectrum hydrolytic capacity and lack of inhi-
bition by tazobactam or clavulanate, metallo-
-lactamases can pro-
vide resistance to the penicillins, inhibitor-penicillin combinations,
and carbapenems [24, 112]. However, metallo-
-lactamases do not
efficiently hydrolyze monobactams [24, 112].
The history and clinical significance of metallo-
-lactamases
have been the focus of two recent reviews [99, 112]. Similar to the
class A carbapenemases described above, metallo-
-lactamases can
be encoded on both the chromosome and mobile genetic elements.
The first transferable metallo-
-lactamase, IMP-1, was identified in
1988 in a clinical isolate P. aeruginosa from Japan [113]. Since this
first report, dozens of transferrable metallo-
-lactamases have been
described globally among isolates of P. aeruginosa, and they be-
long to four distinct families, namely IMP, VIM, GIM, and SPM
[112].
PORIN-MEDIATED RESISTANCE
The outer membrane of P. aeruginosa is an effective antibacte-
rial barrier that is only 8% as permeable as the outer membrane of
Escherichia coli [114]. To aid in the passage of nutrients and other
desired molecules into the cell, P. aeruginosa utilizes a collection
of porin channels. Based on the completed sequence of the P. aeru-
ginosa genome, 64 known or putative porins have been identified
[114]. The following discussion will primarily focus on the well-
characterized association between the OprD porin and carbapenem
susceptibility of P. aeruginosa, but also touch upon the potential
role of OprF in altering
-lactam susceptibility.
OprD and Susceptibility of P. aeruginosa to Carbapenems
The OprD porin of P. aeruginosa is a substrate-specific porin
that facilitates the diffusion of basic amino acids, small peptides,
and carbapenems into the cell [115, 116]. Studies suggest that OprD
214 Current Pharmaceutical Design, 2013, Vol. 19, No. 2
is the preferred portal of entry for carbapenems across the outer
membrane, as decreases or loss of OprD significantly decrease the
susceptibility of P. aeruginosa to available carbapenems [30, 116-
119]. However, recent studies have described strains of P. aerugi-
nosa that exhibit a discordance between OprD absence and suscep-
tibility to carbapenems [33, 120], suggesting other pathways of
carbapenem penetration.
The complex pathways used by P. aeruginosa to regulate levels
of OprD in the outer membrane has been recently reviewed [22],
and include mechanisms that impact oprD expression and mecha-
nisms that influence the production of a functional OprD channel.
Regardless of the pathway, the impact of OprD-mediated resistance
on the carbapenems can be analyzed by comparing carbapenem
susceptibilities according to clinically-significant breakpoints (es-
tablished by the CLSI) with OprD levels.
Although some investigators have concluded from the analysis
of non-controlled clinical isolates that meropenem is unique in hav-
ing alternative pathways of penetration [121], data from a more
recent study of controlled isogenic “wild-type” and OprD-deficient
mutant pairs demonstrated that loss of OprD impacted susceptibility
to meropenem to a greater degree than imipenem or doripenem
[122]. When considering the clinical impact of OprD-mediated
resistance, loss of OprD alone is usually sufficient to push MICs of
imipenem above the resistance breakpoint. This is not surprising
since the MIC50 for imipenem against P. aeruginosa is already at 1
μg/ml [123, 124]. By comparison, wild-type P. aeruginosa are
generally
4-fold more susceptible to meropenem and doripenem
than they are to imipenem, and the impact of OprD-mediated resis-
tance on potency to these carbapenems does not always push MICs
above the susceptible breakpoint. Additional resistance mecha-
nisms, e.g. efflux pump overproduction and/or
-lactamase produc-
tion, may be required to provide clinical resistance to meropenem
and doripenem. For example, studies using laboratory-derived mu-
tants have shown that a combination of OprD loss with either
MexAB-OprM overexpression or AmpC overproduction resulted in
significantly higher MICs to meropenem and doripenem, respec-
tively, compared to porin loss alone [125].
Potential Decrease of
-lactam Susceptibility Through OprF
Loss
The porin, OprF, is a major constituent of the P. aeruginosa
outer membrane and participates in the maintenance of cell shape
[126, 127], supports growth in low osmolarity conditions [128],
potentially serves as a general or nonspecific porin for the passage
of various compounds [128, 129], and has a proposed role in adher-
ence to epithelial cells [130]. Yoon et al. also demonstrated a role
for oprF in biofilm formation, anaerobic growth, and nitrate uptake
[131].
Similar to the effect of OprD loss on carbapenem susceptibili-
ties, loss of OprF has been suggested in a few studies to decrease
the susceptibility of P. aeruginosa to certain -lactams. In the first
study, Piddock et al. reported that a multi-drug resistant strain (in-
cluding resistance to several -lactams such as cefotaxime, ceftaz-
idime, and carbenicillin) of P. aeruginosa that lacked OprF was
isolated from a patient following therapy [132]. Restoration of
OprF production conincided with reversion of -lactam suscepti-
bilities to pre-therapy levels [132]. Secondly, a laboratory-derived
OprF deficient strain of P. aeruginosa had modest increases in
MICs to several -lactams including carbenicillin and cefotaxime
[133]. Loss of OprF may have decreased -lactam susceptibility in
these studies by causing either: 1) diminished -lactam uptake di-
rectly through the OprF channel or 2) altered permeability as the
indirect result of defects in membrane architecture since OprF
serves in anchoring the outer membrane to the peptidoglycan layer
[128, 134]. Regardless, OprF may be another mechanism that can
influence -lactam susceptibilities. Additional studies are needed to
address this possibility.
Wolter and Lister
EFFLUX-MEDIATED RESISTANCE
-lactams that freely diffuse into the P. aeruginosa cell and
escape inactivation by resident -lactamases may encounter another
formidable obstacle in route to their target, extrusion by efflux
pumps. The P. aeruginosa PAO1 genome possesses efflux encod-
ing genes belonging to five different superfamilies [135], but thus
far, only efflux pumps belonging to the resistance-nodulation-
division (RND) family have been shown to participate in -lactam
resistance. The RND family represents the highest number of pre-
dicted pumps within the P. aeruginosa chromosome, 12 total in-
cluding two divalent metal cation transporters, which far exceeds
the RND pumps present on the E. coli chromosome (4 total) [135].
Of these, 3 RND efflux pumps are capable of exporting -lactams,
namely MexAB-OprM, MexCD-OprJ, and MexXY.
The P. aeruginosa RND pumps are assembled with three sepa-
rate components, a periplasmic membrane fusion protein (MFP), an
outer membrane factor (OMF), and a cytoplasmic membrane
(RND) transporter, that form a channel spanning across both the
inner and outer membranes (Fig. 2) [22]. Although the RND pump
creates a passage way from the extracellular milieu to the cyto-
plasm from which substrates may be removed, the architecture of
the pump also permits the recognition and export of compounds
from the periplasmic space, the site of -lactam activity.
Crystallographic examination of a RND component in E. coli,
AcrB (homologous to MexB in P. aeruginosa) [136, 137], and
H+
O
OM
PG
PS
O
CM
MFP RND OMP
Transcription
mfp rnd omp
Fig. (2). Structure and function of RND efflux pumps in P. aeruginosa.
RND pumps typically exist in a tripartite system consisting of an RND
cytoplasmic membrane transporter (RND), a membrane fusion protein
(MFP), and outer membrane factor (OMF). The genes which encode the
pump components are organized into operons, and following translation of
the polycistronic message, the pump components assemble into a channel
that spans across the entire membrane. -lactams enter into the RND trans-
porter through openings known as vestibules and are exported through the
channel to the extracellular milieu using proton-motive force. Figure revised
and reprinted from Lister et al. [22] with permission from the American
Society of Microbiology.
Antibacterial Resistant Pseudomonas aeruginosa
protein modeling of the MexB component in P. aeruginosa [138]
have shown them to exist as a homotrimeric complex with trans-
membrane helices lodged into the cytoplasmic membrane (trans-
membrane domain) and a periplasmic domain that forms a central
cavity. A route from the periplasm to the central cavity exists
through openings, referred to as vestibules, between monomers
along the surface of the cytoplasmic membrane [139].
-lactams in
the periplasm may enter into the RND transporter through these
vestibules. Initial chimeric and mutational studies of E. coli and P.
aeruginosa pumps linked substrate specificity to the cytoplasmic
RND transporter and suggest the location of substrate recognition
occurs within the central cavity [140, 141]. However, more recent
studies have identified a binding pocket within the periplasmic
domain that is connected to the vestibule through an additional
channel, and this pocket serves as the substrate recognition site
[142, 143]. Once inside the binding pocket, RND transporters util-
ize proton-motive force to translocate substrates (e.g.
-lactams)
through the OMF to the extracellular environment. Addition of
compounds that interfere with the proton gradient, such as the pro-
ton uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP),
prevents the efflux of substrates from within the cell [144].
The efflux encoding genes within P. aeruginosa are organized
into operons on the bacterial chromosome (Fig. 2) [22]. mexAB-
oprM, mexCD-oprJ, and mexXY each possess a gene that codes for
the MFP (mexA, mexC, and mexX) and RND transporter (mexB,
mexD, and mexY). The mexAB-oprM and mexCD-oprJ operons also
contain a gene for the OMF (oprM and oprJ) whose product com-
pletes the formation of the tripartite efflux systems. However, an
OMF encoding gene is absent from the mexXY operon. Therefore,
MexXY must associate with other outer membrane protein compo-
nents to create a functional pump. OprM was shown to serve as the
OMF for MexXY [145-147] and several other candidate OMFs
have been proposed including OpmB, OpmG, OpmH, and possibly
OpmI [146, 148]. The regulatory genes mexR, nfxB, and mexZ re-
side directly upstream of mexAB-oprM, mexCD-oprJ, and mexXY,
respectively, and are transcribed divergently from the operon [22].
The products of these regulatory genes bind to operator sites within
the intergenic regions to control expression of the efflux operons
(discussed below).
MexAB-OprM
MexAB-OprM, the first discovered P. aeruginosa RND pump,
contributes to both the intrinsic and adaptive resistance of P. aeru-
ginosa to the
-lactam class of antibiotics. MexAB-OprM is able to
export the widest range of
-lactams among the RND pumps such
as carbenicillin and ticarcillin (carboxypenicillins), piperacillin
(ureidopenicillin), aztreonam (monobactam), ceftazidime and cefo-
taxime (3rd generation cephalosporins), faropenem (penem), and
the carbapenems meropenem and panipenem (excluding imipenem
and biapenem). A recent study showed that overproduction of
MexAB-OprM in a defined laboratory mutant led to slightly ele-
vated MICs for doripenem compared to the parental P. aeruginosa
strain suggesting the recognition and export of this drug at a low
level [125].
-lactam inhibitors (e.g. clavulanate and cloxacillin) are
also substrates for MexAB-OprM [149]. Intrinsic resistance to these

-lactams is attributed to the constitutive expression of mexAB-
oprM in wild-type cells [150]. Deletion of any one component
(mexA, mexB, or oprM) through genetic knockout renders P. aeru-
ginosa hypersusceptible to the
-lactams listed above [151, 152].
Expression of mexAB-oprM is growth-phase dependent in wild-type
cells and is regulated by the N-Butyryl-L-homoserine lactone (C4-
HSL) quorum sensing autoinducer [153, 154].
Although expressed at sufficient levels to influence
-lactam
susceptibility, transcription of the mexAB-oprM operon in wild-type
P. aeruginosa is not fully derepressed. Expression of mexAB-oprM
is initiated from two separate promoters, a distal mexA promoter
that overlaps with the mexR promoter and a proximal mexA pro-
Current Pharmaceutical Design, 2013, Vol. 19, No. 2 215
moter [155]. However, each promoter is occupied by regulatory
proteins that repress the transcription of the efflux operon. MexR, a
regulatory protein of the MarR family [156], binds to cis-acting
sites that encompass the distal mexA promoter, and a trans-acting
repressor of the TetR family, NalD, binds to sequences encom-
passsing the mexA proximal promoter [157].
Loss of MexR-mediated regulation of the distal mexA promoter
causes mexAB-oprM hyperexpression in mutants termed nalB-type
and nalC-type. In nalB-type strains, mutations within mexR can
either truncate the production of full length protein, potentially
diminish protein stability, or compromise MexR functionality by
preventing protein dimerization or DNA binding [158, 159]. nalC-
type mutants retain a wild-type mexR, but mutations in another
gene, nalC (formerly PA3721), indirectly impacts the ability of
MexR to bind to the distal mexA promoter. NalC, a member of the
TetR/AcrR family, suppresses the expression of the PA3720-
PA3719 (renamed ArmR), and inactivation of NalC results in
ArmR overexpression [160, 161]. ArmR is a 53-amino acid antirep-
ressor that binds inside a hydrophobic cavity within the MexR di-
mer and allosterically inhibits MexR from docking with the distal
mexA promoter [162]. nalC-type mutants overexpress mexAB-oprM
at lower levels in comparison to nalB-type mutants, and as a result,
do not have as great of an impact on
-lactam susceptibility than
nalB-type mutants [163]. Hyperexpression of mexAB-oprM from
the proximal mexA promoter occurs in nalD-type mutants as a re-
sult of mutations within nalD. These mutations presumably inter-
fere with the ability of NalD from binding to the operator sequence
associated with the mexA-proximal promoter [157].
MexCD-OprJ
In comparison to MexAB-OprM, the MexCD-OprJ efflux
pump has a more restricted substrate profile for the
-lactams.
MexCD-OprJ is capable of exporting the fourth generation cepha-
losporins (i.e. cefepime, cefpirome, and cefozopran) [164, 165].
Studies have suggested that additional
-lactams, such as the car-
bapenems meropenem and doripenem, may also be exported by
MexCD-OprJ [166, 167]. However, substrate specificities in these
studies were determined using isogenic mutants containing dele-
tions of other efflux systems. The possibility that these deletions
may have triggered changes in other mechanisms that could impact
drug susceptibility can not be ruled out. Nonetheless, overproduc-
tion of MexCD-OprJ does not decrease the susceptibility of P.
aeruginosa mutants to these additional
-lactams [164], but rather,
only impacts the fourth generation cephalosporins. MexCD-OprJ
also differs from MexAB-OprM in that the pump is not detectable
in wild-type cells [165, 168]. As such, MexCD-OprJ does not
contribute to intrinisic
-lactam resistance [169, 170].
Expression of the mexCD-oprJ operon is tightly controlled by
the regulatory factor NfxB, a protein that displays similarity to the
LacI-GalR family [165]. NfxB binds to a cis-acting site within the
nfxB-mexC intergenic region [171] and represses expression of the
efflux operon [165, 171]. Mutations within nfxB (e.g. base substitu-
tions, deletions, IS element disruption) have been suggested to alle-
viate repression of mexCD-oprJ leading to its overexpression in
mutants termed nfxB-type [165, 171-173]. Overproduction of
MexCD-OprJ has been shown to occur at two different levels in
mutants defined as type A and type B. Type A mutants produce
lower amounts of MexCD-OprJ than type B mutants, and as a re-
sult, have a smaller decrease in susceptibility to antibiotics exported
by this pump in comparison to type B mutants [164]. Regardless,
overproduction of MexCD-OprJ in both types of mutants is de-
pendent on alterations within NfxB [164].
MexXY
The third RND efflux system responsible for
-lactam resis-
tance in P. aeruginosa is the MexXY pump. As mentioned above,
an OMF encoding gene is absent from the mexXY operon, but in-
216 Current Pharmaceutical Design, 2013, Vol. 19, No. 2
stead, MexXY associates with OprM [145-147] and possibly other
candidate OMFs [146, 148] to form a tripartite pump. MexXY has a
similar substrate profile to the MexCD-OprJ pump with its ability
to export fourth generation cephalosporins [166, 174] but differs
from MexCD-OprJ in that MexXY accommodates the removal of
the "fifth generation" cephalosporin ceftobiprole [175, 176]. mexXY
expression in P. aeruginosa is inducible when cells are exposed to
ribosomal inhibitors (e.g. tetracycline, erythromycin, and gentami-
cin) [177], but expression does not increase when challenged with
sub-inhibitory concentrations of cefepime [178]. Thus, MexXY
most likely does not contribute to intrinsic
-lactam resistance in
wild-type cells.
Expression of mexXY is negatively regulated by MexZ whose
gene is located directly upstream of the efflux operon. MexZ, a
member of the TetR regulatory family, binds to an inverted repeat
sequence within the mexZ-mexX intergenic region and blocks ac-
cess of the RNA polymerase to the putative mexXY promoter [179].
Overexpression of mexXY has been associated with mutations in
mexZ or the mexZ-mexX intergenic region in mutants termed agrZ-
type [180]. However, P. aeruginosa strains hyperexpressing mexXY
but lacking mutations within these sites, called agrW-type mutants,
have also been described [180]. mexXY overexpression in agrW-
type mutants has recently been linked to a two-component regula-
tory system, ParRS [181].
Contribution of Efflux to
-lactam Resistance in Clinical Iso-
lates
Numerous studies have detected the overexpression of an RND
efflux pump in
-lactam resistant P. aeruginosa clinical isolates
suggesting their participation in the resistant phenotype. MexAB-
OprM hyperexpressing clinical isolates have been observed for
each of the nal (B, C, and D)-type mutants and have often been
identified in studies examining the mechanism(s) associated with
carbapenem resistance in P. aeruginosa [182-186]. mexXY overex-
pressing agrZ- and agrW-type mutants from the clinical setting
have also been encountered frequently [187-191]. MexCD-OprJ
overproducing clinical isolates have been described in the literature
[192-194] but are not as common as the other pump mutants, possi-
bly suggesting a disadvantage for P. aeruginosa that utilize this
resistance mechanism. Indeed, studies have shown that nfxB-type
mutants have diminished fitness and virulence traits [195-197].
Overexpression of the RND efflux pumps typically reduces the
susceptibility (2-8-fold decrease in MIC) of P. aeruginosa to
-
lactams that are substrates for a particular pump, but clinical resis-
tance (according to CLSI breakpoints) often requires the involve-
ment of an additional resistance mechanism. For example, nalB-
type mutants have decreased susceptibility to meropenem, but full
resistance occurs with a concomittant loss of OprD [117]. The
combination of OprD loss and MexAB-OprM overepxression has
been detected in several meropenem resistant clinical isolates [198-
200]. Additional combinations of
-lactam resistance mechanisms
have been reported including the simultaneous overexpression of
two efflux pumps. Several groups have detected the co-
hyperexpression of MexAB-OprM and MexXY in resistant P.
aeruginosa [180, 201, 202]. Efflux pump overexpression has been
discovered in isolates with concurrent chromosomal AmpC derep-
ression [203-206] or when harboring an acquired
-lactamase (e.g.
OXA, GES) [174, 207]. Isolates have even been encountered con-
taining at least three different
-lactam resistance mechanisms
(OprD loss, pump hyperexpression, and
-lactamase production)
[107, 208, 209]. The repeated identification of efflux overexpress-
ing P. aeruginosa clinical isolates, either alone or in combination
with other mechanisms, highlights their importance in
-lactam
resistance.
Pseudomonas aeruginosa
-LACTAM RESISTOME
The mechanisms discussed so far in this review are typically
considered as the predominant contributors to
-lactam resistance in
Wolter and Lister
P. aeruginosa and have been analyzed quite extensively as a result
of their impact on drug susceptibility. However, recent studies us-
ing more global screening methods (e.g. analysis of transposon
mutant libraries and proteomics) have indicated that additional
genetic determinants may participate in decreasing
-lactam suscep-
tibility [210-212]. One such library, the Harvard PA14 nonredun-
dant library, represents a collection of mutants in which nonessen-
tial genes have been inactivated by a single transposon insertion
[213]. This library has been used by two independent research
groups to identify genes that directly cause
-lactam resistance
when inactivated or indirectly by increasing the mutational fre-
quency [210, 211].
Susceptibility testing of mutants in the PA14 library to various

-lactams revealed novel genes responsible for altering
-lactam
susceptibility. Many of these genes participate in the synthesis of
the bacterial cell wall or lipopolysaccharide (LPS) including: galU
(PAO1 ortholog PA2023), a UDP-glucose pyrophosphorylase re-
sponsible for synthesis of a complete LPS core, and wbpM (PAO1
ortholog PA3141), a UDP-N-acetylglucosamine 4,6-dehydratase
essential for the biosynthesis of B-band LPS. Inactivation of genes
within a large 17 ORF gene cluster (PA4996–PA5012) that are
involved in the assembly of the core oligosaccharide component of
LPS were also identified by both research groups as causing de-
creased
-lactam susceptibility [210, 211]. Alterations in cell wall
and LPS architecture are believed to decrease the penetration of
-
lactams into the periplasmic space. Various modifications in LPS
composition were previously shown to either decrease [214, 215] or
increase [216]
-lactam susceptibility in P. aeruginosa supporting
the role of LPS in antibiotic uptake.
Besides genes involved with cell wall and LPS synthesis,
analysis of the PA14 library has identified additional genes with
diverse functions that alter
-lactam susceptibility when deleted.
Inactivation of genes that participate in chemotaxis and biofilm
formation (wspE, a histidine kinase-response regulator and wspR, a
diguanylate cyclase), amino acid metabolism (aroB, a 3-
dehydroquinate synthetase), carbon compound catabolism and en-
ergy metabolism (PA5192, a phosphoenolpyruvate carboxykinase),
and transcriptional regulation (PA0479, regulator of the LysR fam-
ily) all decreased susceptibility of P. aeruginosa to several
-
lactams [210, 211]. It is unknown at this time how the loss of these
genes influence
-lactam susceptibility. However, these results
illustrate the vast array of mechanisms capable of altering suscepti-
bility of P. aeruginosa to
-lactams.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of
interest.
ACKNOWLEDGEMENT
Declared none.
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