The intrinsic resistome of Pseudomonas aeruginosa to β-lactams

Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
Virulence (Impact Factor: 4.22). 03/2011; 2(2):144-6. DOI: 10.4161/viru.2.2.15014
Source: PubMed
ABSTRACT
Pseudomonas aeruginosa is a relevant opportunistic pathogen particularly problematic due to its low intrinsic susceptibility to antibiotics. Intrinsic resistance has been traditionally attributed to the low permeability of cellular envelopes together with the presence of chromosomally-encoded detoxification systems such as multidrug efflux pumps or antibiotic inactivating enzymes. However, some recently published articles indicate that several other elements can contribute to the phenotype of intrinsic resistance of bacterial pathogens. In a recently published article, we explored the chromosomally-encoded determinants that contribute to the phenotype of susceptibility of P. aeruginosa to ceftazidime, imipenem and carbapenem. Using a comprehensive library of transposon-tagged insertion mutants, we found 37 loci in the chromosome of P. aeruginosa that contributed to its intrinsic resistance, because mutants in these loci were more susceptible to antibiotics than their parental strain. 41 further loci could potentially be involved in the acquisition of resistance, because mutants in these loci were less susceptible than their wild-type counterpart. These results indicate that the intrinsic resistome of P. aeruginosa involves several elements, belonging to different functional families and cannot be considered as a specific mechanism of adaptation to the recent usage of antibiotics as therapeutic agents. In the current article, we summarize the findings of the paper and discuss their implications for understanding the evolution of antibiotic resistance and for defining novel targets for the search of new antimicrobials. Finally, the validity of recent theories on the mechanisms of action of antibiotics is discussed taken into consideration the results of our paper and other recently published works on the mechanisms of intrinsic resistance to antibiotics of P. aeruginosa.

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Virulence 2:2, 144-146; March/April 2011; © 2011 Landes Bioscience
AUTOPHAGIC PUNCTUM
144 Virulence Volume 2 Issue 1
Addendum to: Alvarez-Ortega C, Wiegand I,
Olivares J, Hancock REW, Martinez JL. Genetic
determinants involved in the susceptibility
of Pseudomonas aeruginosa to beta-lactam
antibiotics. Antimicrob Agents Chemother
2010; 54:4159–67; PMID: 20679510; DOI: 10.1128/
AAC.00257-10.
Key words: Intrinsic resistance,
Pseudomonas aeruginosa, b-lactam resis-
tance, b-lactamase, resistome
Submitted: 12/03/10
Revised: 01/31/11
Accepted: 01/31/11
DOI: 10.4161/viru.2.2.15014
Correspondence to: José Luis Martínez;
Email: jlmtnez@cnb.csic.es
The intrinsic resistome of Pseudomonas aeruginosa to b-lactams
Carolina Alvarez-Ortega,
1
Irith Wiegand,
2
Jorge Olivares,
1
Robert E.W. Hancock
3
and José Luis Martínez
1,
*
1
Departamento de Biotecnoloa Microbiana; Centro Nacional de Biotecnología; CSIC; Madrid, Spain;
2
AiCuris GmbH & Co. KG; Wuppertal, Deutschland;
3
Department of Microbiology and Immunology; Centre for Microbial Diseases and Immunity Research; University of British Columbia; Vancouver, BC Canada
P
seudomonas aeruginosa is a relevant
opportunistic pathogen particu-
larly problematic due to its low intrinsic
susceptibility to antibiotics. Intrinsic
resistance has been traditionally attrib-
uted to the low permeability of cellular
envelopes together with the presence of
chromosomally-encoded detoxification
systems such as multidrug efflux pumps
or antibiotic inactivating enzymes.
However, some recently published
articles indicate that several other ele-
ments can contribute to the phenotype
of intrinsic resistance of bacterial patho-
gens. In a recently published article, we
explored the chromosomally-encoded
determinants that contribute to the phe-
notype of susceptibility of P. aeruginosa
to ceftazidime, imipenem and carbape-
nem. Using a comprehensive library of
transposon-tagged insertion mutants,
we found 37 loci in the chromosome of
P. aeruginosa that contributed to its
intrinsic resistance, because mutants
in these loci were more susceptible to
antibiotics than their parental strain.
Forty one further loci could potentially
be involved in the acquisition of resis-
tance, because mutants in these loci
were less susceptible than their wild-type
counterpart. These results indicate that
the intrinsic resistome of P. aeruginosa
involves several elements, belonging to
different functional families and cannot
be considered as a specific mechanism of
adaptation to the recent usage of antibi-
otics as therapeutic agents. In the current
article, we summarize the findings of the
paper and discuss their implications for
understanding the evolution of antibiotic
resistance and for defining novel targets
for the search of new antimicrobials.
Finally, the validity of recent theories on
the mechanisms of action of antibiotics
is discussed taken into consideration the
results of our paper and other recently
published works on the mechanisms
of intrinsic resistance to antibiotics of
P. aeruginosa.
Antibiotic resistance is frequently con-
sidered as an acquired trait of bacterial
populations, which has become promi-
nent very recently (in evolutionary terms)
as the consequence of the introduction
of antibiotics for the treatment of infec-
tious diseases.
1,2
Since resistance can be
achieved either as the consequence of
mutation
3
or due to the horizontal acqui-
sition of resistance genes,
4
it has been
largely assumed that the origin of such
resistance genes are the microorganisms
producing antibiotics, since they need
to carry resistance elements to avoid the
inhibitory action of the antibiotics they
produce.
5,6
Possibly due to these views
regarding the origins of resistance, and
the forces that shape its evolution, intrin-
sic resistance has not been analyzed in
full detail until recently. It is of critical
importance in opportunistic pathogens
that present a characteristic low natu-
ral susceptibility to antibiotics. Intrinsic
resistance has traditionally been attrib-
uted to a reduced permeability of the cell
envelope due to decreased uptake. This is
a dependent mechanism in the sense that
restricted permeability is hard-wired into
the cell and slows down rather than pre-
vents the uptake of antibiotic. The char-
acterization of chromosomally-encoded
antibiotic-inactivating enzymes (such
as b-lactamases) and multidrug (MDR)
efflux pumps demonstrated that bacterial
Page 1
©2011 Landes Bioscience.
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www.landesbioscience.com Virulence 145
AUTOPHAGIC PUNCTUM
ARTICLE ADDENDUM
cells harbor further intrinsic mecha-
nisms that can act in synergy with slowed
uptake to reduce the activity of the antibi-
otics. Differing from reduced permeabil-
ity, the latter are detoxification elements
that resemble the classical determinants
of antibiotic resistance acquired by hori-
zontal gene transfer. However, since these
elements are widespread, can be encoded
in the core-genome and, in the case of
MDR efflux pumps, are present in the
chromosomes of all organisms, including
those that do not produce antibiotics,
7,8
they might have evolved for purposes
other than just avoiding the activity of
a given antibiotic. Indeed, the recent
analyses of comprehensive transposon-
tagged mutant libraries in different
organisms such as Escherichia coli
9,10
or
Pseudomonas aeruginosa
11-14
demonstrated
the existence of several genes that cause
changes in antibiotic susceptibility when
they are inactivated. Among those genes,
several encode for proteins involved in
bacterial metabolism, indicating that
intrinsic antibiotic resistance is not just
the consequence of bacterial adaptation
to the presence of antibiotics, but rather
a characteristic phenotype highly depen-
dent on the metabolic networks of each
bacterial species. Indeed it may reflect
an adaptation to a distinct growth state
such as afforded by biofilm development
and swarming motility both of which are
multigenic phenomena associated with
major increases in antibiotic resistance
and metabolic changes.
15,16
In a recent paper, we analyzed a com-
prehensive library of transposon-tagged
insertion mutants with the aim of find-
ing genes that changed the susceptibil-
ity of P. aeruginosa to b-lactams upon
inactivation.
17
This bacterial species is
one of the most important opportunistic
pathogens,
18
causing severe infections in
hospitals and being the major pathogen
associated with eventually fatal chronic
infections that afict patients with cys-
tic fibrosis, the most prevalent inher-
ited disease in Caucasian populations.
P. aeruginosa is particularly problematic
due to its low intrinsic antibiotic suscep-
tibility
19
in part based on its exceptionally
low outer membrane permeability.
20
The
antibiotics chosen for the analysis were
a cephalosporin (ceftazidime) and two
carbapenems (meropenem and imipe-
nem) that are currently used for treating
P. aeruginosa infections. Two carbapen-
ems were included in order to check
whether intrinsic resistance to drugs
belonging to the same structural family
might have some degree of specificity.
We studied mutants that showed a higher
susceptibility, reflecting proteins that
contribute to intrinsic resistance, as well
as mutants with decreased susceptibil-
ity, which define the genetic reservoir of
P. aeruginosa for evolving towards resis-
tance without acquiring foreign DNA.
One of our main objectives was to
look for small changes in antibiotic sus-
ceptibility. Antibiotic resistance can be
defined using operational criteria, which
take into account the pharmacokinetics
and pharmacodynamics of the antibiot-
ics to establish those values above which
a therapeutically useful concentration is
difficult to achieve. If the MIC for a bac-
terium is above these values, a risk exists
that the infection cannot be successfully
treated. Because of this, it is usually
assumed that the microorganisms should
be categorized as resistant when their
MICs are above a pre-defined threshold.
This denition, which has a clear rele-
vance in the clinical world, does not take
into consideration low-level resistance
mechanisms. In our work we took into
consideration this type of mutants because
low-level resistance is relevant to the
development of high level resistance
21,22
and is also likely the cause of MIC-creep,
defined as the constant rise over time in
the basal intrinsic resistance of an average
isolate of a given bacterial species.
23
Low-
level resistance is difficult to track using
conventional double-dilution tests of
antibiotic susceptibility. Because of this,
we confirmed our screen results by deter-
mining MICs using the Epsilon-Test,
which allows for the accurate discrimi-
nation between small changes in MIC
values. Applying a threshold on MIC
change of two-fold, we found that 37 loci
in the chromosome of P. aeruginosa con-
tributed to its intrinsic resistance to anti-
biotics (mutants in these loci were more
susceptible than their wild-type parental
strain), whereas 41 could potentially be
involved in the acquisition of resistance
upon their inactivation (mutants in these
loci were less susceptible than the wild-
type). As these studies were restricted to
transposon mutants it is likely that there
are other genes in the resistome that can-
not be knocked out due to their essenti-
ality for growth on common lab media.
Additionally other proteins expressed in
infection of the host may not be expressed
in vitro and such proteins contributing to
the resistome would not have been found
in our study.
The antibiotics used in our screen
affect cell wall synthesis by interacting
with penicillin-binding proteins and
murein hydrolases, therefore we expected
to detect a core set of loci involved in the
susceptibility to this family of antibiot-
ics. To our surprise, the overlap among
the different phenotypes was very low.
Only one mutant (in PA0908) presented
reduced susceptibility to all three antibi-
otics and two (in glnK and ftsK ) showed
an increased susceptibility to all three
antibiotics. These last two mutants
revealed genes that are potential good
targets in looking for drugs that, like
the b-lactamase inhibitors, increase the
efficacy of antibiotics against resistant
organisms.
Those genes that when inactivated
resulted in changes in susceptibility to
b -lactams encode for proteins that belong
to a variety of functional groups, includ-
ing metabolic enzymes such as phospho-
enolpyruvate carboxiquinase, elements
involved in cell attachment and motility
such as fimbrial proteins or chemotaxis
proteins, elements involved in the biosyn-
thesis of LPS and in alginate production,
and transcriptional regulators. More clas-
sical resistance elements such as the trans-
porter of carbapenems, OprD2, regulators
of efflux pumps like NalC, elements of
these efflux pumps, like OprM or elements
involved in the regulation of the expres-
sion of the P. aeruginosa chromosomally-
encoded b-lactamases, like those encoded
by dacB, mpl, ampR and ampD emerged
as well in our screening further validating
our experimental approach. Altogether our
results indicate that the intrinsic resistome
of P. aeruginosa involves several differ-
ent elements and might be considered as
an emergent property of the system more
than a specific mechanism of adaptation
to the presence of antibiotics. A recently
Page 2
©2011 Landes Bioscience.
Do not distribute.
146 Virulence Volume 2 Issue 1
published theory on the mechanism of
action of bactericidal antibiotics suggests
that they share a common pathway in
bacterial killing involving the generation
of oxygen radicals, through the interfer-
ence of such antibiotics with the bacte-
rial metabolism.
24,25
From this model, it
can be predicted that mutations in genes
coding for proteins involved in the bacte-
rial metabolism might be relevant in the
development of resistance or supersuscep-
tibility. Unfortunately, our results did not
support a general role of oxygen radicals
in killing. Indeed although some of the
mutations analyzed in our work were pre-
viously found to be involved in the intrin-
sic resistance of P. aeruginosa to other
drugs, most of the mutants were specific,
indicating that the mechanisms of activ-
ity of the antibiotics and thus the mecha-
nisms of intrinsic resistance are not as
general as might be expected based on the
common pathway concept. Furthermore,
the percentage of mutants presenting the
same phenotype (increased or decreased
susceptibility) for imipenem and merope-
nem was not high, despite both antibiotics
being carbapenems. Another interesting
issue, raised as well in other studies on
intrinsic resistomes
26
is the finding of some
degree of strain-specificity. Whereas some
elements contributed to resistance in both
P. aeruginosa strains PAO1 and PA14,
others are strain-specific. This might be
due to different expression levels of these
elements in either of the strains or to the
existence of changes in their respective
metabolic and/or regulatory networks.
As a conclusion of our work, and con-
sistent with other published studies, it
can be stated that the intrinsic resistome
of P. aeruginosa involves a large array of
elements. Furthermore, the analysis of
mutants causing a reduced susceptibility
to b-lactams indicates that this bacte-
rial species has a high potential to evolve
towards resistance. Given that mutation
is the main mechanism whereby P. aeru-
ginosa develops resistance during chronic
infections,
27,28
the results presented in
our article and others dealing with the
intrinsic resistome of this bacterial patho-
gen might help to define novel elements
involved in the acquisition of resistance
during such infections.
Acknowledgements
Research in JLM laboratory was supported
by BIO2008-00090 from the Spanish
Ministerio de Ciencia e Innovación,
and KBBE-227258 (BIOHYPO) and
HEALTH-F3-2010-241476 (PAR) from
European Union. REWH was supported by
the Canadian Cystic Fibrosis Foundation.
CA is the recipient of a JAE contract from
CSIC. JO is the recipient of a fellowship
from Programa Beca Chile, CONICYT.
REWH holds a Canada Research
Chair. IW thanks the Juergen Manchot
Foundation and the Mukoviszidose e.V.,
Bonn, Germany (German Cystic Fibrosis
Association), for financial support.
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  • Source
    • "Reduced penetration of antimicrobial molecules EPS323334 Physiological gradients [21,39,40] Formation of persister cells [45,46] General stress response rpoS, anr [51,52] The second Cell wall Peptidoglycan [64,65] Cell membrane Membrane proteins727374 Action of efflux pumps AcrAB/TolC, MexAB-oprM, MexCD-OprJ, MexEF-oprN, MexXY-oprM [ Increasing the production of a metabolite PABA [5] Quorum sensing (QS) systems LasR-LasI, RhlR-RhlI [119,121,122] DNA synthesis DNA gyrase, topoisomerase IV [125,126] RNA synthesis RNAP, rRNA methylases128129130 Plasmid mediated resistance ermC, cfr, β-lactamase, qnr [131,133,135136137138139140142,144] Mutations of the target gene in bacterial chromosome gyrA, parC, parE, marOR, acrR [148] Transposon [153,154155156 Integrons intI, attI, Pc, arr-2164165166 Resistome 171172173 * The listed cases represent only a part of examples in a given resistance mechanism, not for all. "
    [Show abstract] [Hide abstract] ABSTRACT: Antimicrobial agents target a range of extra- and/or intracellular loci from cytoplasmic wall to membrane, intracellular enzymes and genetic materials. Meanwhile, many resistance mechanisms employed by bacteria to counter antimicrobial agents have been found and reported in the past decades. Based on their spatially distinct sites of action and distribution of location, antimicrobial resistance mechanisms of bacteria were categorized into three groups, coined the three lines of bacterial defense in this review. The first line of defense is biofilms, which can be formed by most bacteria to overcome the action of antimicrobial agents. In addition, some other bacteria employ the second line of defense, the cell wall, cell membrane, and encased efflux pumps. When antimicrobial agents permeate the first two lines of defense and finally reach the cytoplasm, many bacteria will make use of the third line of defense, including alterations of intracellular materials and gene regulation to protect themselves from harm by bactericides. The presented three lines of defense theory will help us to understand the bacterial resistance mechanisms against antimicrobial agents and design efficient strategies to overcome these resistances.
    Full-text · Article · Sep 2015 · International Journal of Molecular Sciences
  • Source
    • "P. aeruginosa is one of the most important nosocomial pathogens that cause severe wound infections in burn patients [42], chronic lung infections preferably in cystic fibrosis patients [43] or other hospital acquired infections like urinary tract infections due to formation of biofilms in catheters [44]. P. aeruginosa displays a high ability to resist antibiotics intrinsically [45] but multidrug resistance occurs even by acquisition of resistance genes, over-expression of efflux pumps, decreased expression of porins or mutations. P. aeruginosa is even able to metabolize sodium dodecyl sulfate (SDS), a biocide detergent to all known bacteria so far [46]. "
    [Show abstract] [Hide abstract] ABSTRACT: Photodynamic inactivation of bacteria (PIB) proves to be an additional method to kill pathogenic bacteria. PIB requires photosensitizer molecules that effectively generate reactive oxygen species like singlet oxygen when exposed to visible light. To allow a broad application in medicine, photosensitizers should be safe when applied in humans. Substances like vitamin B2, which are most likely safe, are known to produce singlet oxygen upon irradiation. In the present study, we added positive charges to flavin derivatives to enable attachment of these molecules to the negatively charged surface of bacteria. Two of the synthesized flavin derivatives showed a high quantum yield of singlet oxygen of approximately 75%. Multidrug resistant bacteria like MRSA (Methicillin resistant Staphylococcus aureus), EHEC (enterohemorrhagic Escherichia coli), Pseudomonas aeruginosa, and Acinetobacter baumannii were incubated with these flavin derivatives in vitro and were subsequently irradiated with visible light for seconds only. Singlet oxygen production in bacteria was proved by detecting its luminescence at 1270 nm. After irradiation, the number of viable bacteria decreased up to 6 log10 steps depending on the concentration of the flavin derivatives and the light dosimetry. The bactericidal effect of PIB was independent of the bacterial type and the corresponding antibiotic resistance pattern. In contrast, the photosensitizer concentration and light parameters used for bacteria killing did not affect cell viability of human keratinocytes (therapeutic window). Multiresistant bacteria can be safely and effectively killed by a combination of modified vitamin B2 molecules, oxygen and visible light, whereas normal skin cells survive. Further work will include these new photosensitizers for topical application to decolonize bacteria from skin and mucosa.
    Full-text · Article · Dec 2014 · PLoS ONE
  • Source
    • "Although increased resistance can also be achieved because of the induction of specific resistance mechanisms (for instance induction of chromosomally-encoded -lactamases by -lactams [7]), this topic is not usually considered as phenotypic resistance and will not be discussed in the article. Some recent works have analyzed the determinants that contribute to the intrinsic resistance (intrinsic resistome) of bacterial pathogens8910111213141516. Notably, in all cases in which a comprehensive study has been performed the number of genes involved in the phenotype of resistance is larger than could be predicted if they had evolved as specific elements for counteracting the action of the drugs. "
    Preview · Article · Jun 2013
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