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Antimicrobial Agents and Chemotherapy, June 2001, p. 1930-1933, Vol. 45, No. 6
Department of Microbiology, Toho University
School of Medicine, Tokyo, Japan,1 and
Department of Microbiology and Genetics, University of
Geneva, Geneva, Switzerland2
Received 9 October 2000/Returned for modification 17 January
2001/Accepted 28 March 2001
We report that 2 µg of azithromycin/ml inhibits the
quorum-sensing circuitry of Pseudomonas aeruginosa strain
PAO1. Addition of synthetic autoinducers partially restored the
expression of the trancriptional activator-encoding genes
lasR and rhlR but not that of the autoinducer
synthase-encoding gene lasI. We propose that azithromycin
interferes with the synthesis of autoinducers, by an unknown mechanism,
leading to a reduction of virulence factor production.
Pseudomonas aeruginosa is
a major bacterial pathogen in patients suffering from cystic fibrosis
(CF) or diffuse panbronchiolitis (DPB) (7). Macrolides,
such as azithromycin, are normally not included in the antipseudomonal
therapeutic arsenal because of the absence of bactericidal or
bacteriostatic activity. However, several studies have highlighted the
benefit of long-term macrolide treatment in patients suffering from DPB
or CF (5, 10). The mechanisms by which macrolides affect
the outcome of chronic infections with P. aeruginosa could
include an anti-inflammatory activity and/or a modulation of the
production of bacterial virulence factors (9). Macrolides
inhibit the production of bacterial exoproteases; however, whether this
is independent of a decrease in bacterial growth and total protein
production is controversial (13, 14, 19, 24, 25).
In P. aeruginosa, the las and rhl
quorum-sensing systems regulate the production of several extracellular
virulence factors, including elastase and rhamnolipid
(27). Each system is composed of a gene encoding a
transcriptional activator, lasR and rhlR, and a
gene encoding an autoinducer synthase, lasI and
rhlI, required for the synthesis of the autoinducer
molecules 3-oxo-C12-homoserine lactone
(3-oxo-C12-HSL) (15) and C4-HSL
(16), respectively. The importance of quorum sensing in
the pathogenesis of chronic infections is unknown. P. aeruginosa isolates from CF patients produce autoinducers
(6), and autoinducer production by CF sputum has been
associated with P. aeruginosa biofilms (22). Autoinducers have also been found in lung tissue of mice infected with
P. aeruginosa (29). A reduction of autoinducer
production by 50 µg of erythromycin/ml has been suggested
(23). However, the Chromobacterium violaceum
bioassay used could only measure the C4-HSL autoinducer
(11).
We wondered whether azithromycin interferes with the quorum-sensing
circuitry. To differentiate the inhibition of virulence factor
production from a nonspecific effect, we optimized our experimental
conditions so that at the onset of stationary phase, when quorum
sensing is active, growth was not notably affected. Figure
1A shows growth curves of wild-type PAO1
(8) in the presence of increasing concentrations of
azithromycin. Exponential growth was slightly affected in the presence
of 2 µg of azithromycin/ml, but no effect on the stationary growth
phase was observed. Sodium dodecyl sulfate-polyacrylamide gel
electrophoresis of total protein extracts of cells grown either in the
absence or the presence of 2 µg of azithromycin/ml did not reveal
major differences (data not shown). We next determined the effect of 2 µg of azithromycin/ml on elastase and rhamnolipid production in
strain PAO1. Elastase production was monitored using elastin Congo red
assays (17). In accordance with previous reports
(13, 14), azithromycin inhibited the production of
elastase (Fig. 1B). To determine the effect of azithromycin on
rhamnolipid production, we used an azithromycin gradient incorporated
into M9-based agar plates (21). The production of
rhamnolipids progressively decreased with increasing azithromycin concentrations without a parallel drop in growth (data not shown). To
reveal a possible effect on rhlAB transcription, we measured
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.6.1930-1933.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Azithromycin Inhibits Quorum Sensing in Pseudomonas
aeruginosa
ABSTRACT
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-galactosidase (-Gal) activity (12) using the
rhlA'-lacZ reporter fusion pECP60 (18). The
expression of rhlAB was strongly inhibited by the macrolide
(Fig. 1C), thus confirming the results from the plate assays.
Interestingly, no inhibition of virulence factor production was
observed when the antibiotic was omitted in the overnight preculture,
suggesting that prolonged exposure to the antibiotic is required.
Subsequently, we determined the effect of azithromycin on the
expression of the two transcriptional activator genes, lasR
and rhlR, using the reporter fusions
pPCS1001(lasR'-lacZ) (18) and
pPCS1002(rhlR'-lacZ) (18). Azithromycin reduced
the expression of both reporter fusions (Fig.
2A). We further investigated whether the
macrolide also affects the expression of the two autoinducer synthase
genes, lasI and rhlI, by using the reporter
fusions pPCS223(lasI'-lacZ) (28) and
pLPRI(rhlI'-lacZ) (28). Azithromycin reduced
the transcription of lasI by 80% and of rhlI by
50% (Fig. 2B). To ensure that this inhibition was effectively
associated with a decreased production of the 3-oxo-C12-HSL
and C4-HSL signaling molecules, we extracted these two
autoinducers from bacterial supernatants and measured their respective
concentrations using specific bioassays (17, 20). In the
presence of the macrolide, the concentrations of
3-oxo-C12-HSL and C4-HSL were reduced by 94 and
72%, respectively (Fig. 3A). We also
measured the effect of azithromycin on the expression of the
xcpR gene, which codes for a structural protein belonging to
the type II secretion pathway (1, 2), by using the
transcriptional reporter fusion pMPR(xcpR'-lacZ) (3). The transcription of xcpR was not affected
by azithromycin (2,741 ± 37 Miller units versus 2,760 ± 25 Miller units, respectively; mean of three experiments ± standard
deviation [SD], measured at an optical density at 660 nm of 4.8).
These results seem to be in contradiction with a previous report
suggesting that xcpR transcription is positively regulated
by the las system (3). This apparent
discrepancy could be explained by dissimilar experimental conditions
and the use of different laboratory strains. Another explanation could
be the compensation by other, already previously suspected
(3), regulatory pathways maintaining xcpR
expression despite the inhibition of the las quorum-sensing
system by azithromycin. Since the expression of both lasR
and rhlR genes is dependent on the presence of adequate
autoinducer levels, we measured their transcription in the presence of
exogenous synthetic 3-oxo-C12-HSL and C4-HSL,
each provided at concentrations of 10 µM. The addition of both
autoinducers completely restored the expression of rhlR and
almost completely restored the expression of lasR
(5,500 ± 600 Miller units in the absence of azithromycin versus
4,600 ± 300 Miller units in the presence of azithromycin and
exogenous autoinducers) (Fig. 2A). In contrast, the addition of
exogenous autoinducers could not restore the expression of the
lasI autoinducer synthase gene (20% of initial value in the
presence of azithromycin and 16% in the presence of both azithromycin
and exogenous autoinducers; data not shown). The addition of exogenous
autoinducers also partially restored the production of elastase and
almost completely restored the expression of rhlAB (Fig.
3B). These results suggest that azithromycin might reduce the
production of quorum-sensing-dependent virulence factors by inhibiting
the synthesis of the autoinducer molecules.
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FIG. 1.
Effect of azithromycin on growth and elastase and
rhamnolipid production. (A) Bacterial strains were grown in
Luria-Bertani (LB) medium in the absence (squares) or in the presence
(circles, 2 µg/ml; upside triangles, 3 µg/ml; downside triangles, 4 µg/ml; diamonds, 5 µg/ml) of azithromycin. Growth curve
determinations were repeated five times and the graph shows results
from one typical experiment. (B) Supernatants of cells, grown either in
the absence (squares) or the presence (circles) of 2 µg of
azithromycin/ml, were collected at regular intervals and elastase
activity was determined by the elastin Congo red assay. (C)
PAO1(pECP60) (rhlA'-lacZ) was grown in LB medium either in
the absence (squares) or the presence (circles) of 2 µg of
azithromycin/ml, and -Gal activities were assayed at regular time
intervals. Inserted graphs in panels B and C show the corresponding
growth curves. Results are the mean ± SD of three independent
experiments performed in duplicate.
View larger version (20K):
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FIG. 2.
Azithromycin affects transcription of quorum-sensing
genes. The expression of the transcriptional activator and the
autoinducer synthase genes was measured by -Gal determinations in
strain PAO1 cultures grown for 10 h in the absence (azithromycin
) or presence (azithromycin +) of 2 µg of azithromycin/ml, using
plasmids pPCS1001(lasR'-lacZ) and
pPCS1002(rhR'-lacZ) (A) and plasmids
pPCS223(lasI'-lacZ) and pLPRI(rhlI'-lacZ) (B).
Exogenous autoinducers were added to the cell culture as indicated
(autoinducers +). Results are the mean ± SD of three independent
experiments performed in duplicate.
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[in a new window]
FIG. 3.
Autoinducers are reduced in the presence of azithromycin
and partially restore rhlAB expression and elastase
production. (A) Strain PAO1 cultures were grown for 12 h in
Luria-Bertanimedium, either in the absence (azithromycin ) or
presence (azithromycin +) of 2 µg of azithromycin/ml. The
supernatants were extracted with ethyl acetate, and the
3-oxo-C12-HSL and C4-HSL concentrations were
measured using specific bioassays. Results are the mean ± SD of
three independent experiments. (B) Cells were grown for 10 h in
the absence (azithromycin ) or presence (azithromycin +) of 2 µg of
azithromycin/ml and in the absence (autoinducers ) or presence
(autoinducers +) of exogenous autoinducers. The expression of the
rhlAB gene was determined by measuring the -Gal activity
of the rhlA'-lacZ reporter fusion pECP60. The production of
elastase was determined by the elastin Congo red assay performed on
culture supernatants. Results are expressed as the percentage of the
maximum observed in each individual experiment and represent the
mean ± SD of three independent experiments performed in
duplicate.
How does azithromycin interfere with the transcription of genes belonging to the quorum-sensing circuitry? The absence of a reduction of xcpR transcription suggests that, in our experimental conditions, azithromycin does not inhibit the transcription of genes in a nonspecific manner. Azithromycin inhibits protein synthesis at the ribosomal level, and therefore a direct effect on gene transcription seems unlikely. The necessity of a prolonged exposure to azithromycin suggests an indirect effect on the quorum-sensing circuitry. As the expression of lasI could not be complemented by exogenous autoinducers, we hypothesize that azithromycin might interfere with the translation of a so-far-unidentified protein important for the transcription of the autoinducer synthase. A reduced level of autoinducer could explain the observed effects on the quorum-sensing circuitry.
Chronic infections by P. aeruginosa lead to serious deterioration of lung function in DPB and CF patients. The recent reports showing improvement in DPB and CF patients treated with macrolides have been encouraging (5, 10). Our data show a clear inhibition of the quorum-sensing circuitry of P. aeruginosa by azithromycin. Most of the quorum-sensing-regulated virulence factors cause tissue damage. Moreover, the 3-oxo-C12-HSL autoinducer has some immunomodulatory activity (26) and stimulates the production of interleukin-8 by respiratory epithelial cells (4). Therefore, this autoinducer might itself be responsible for a chronic inflammatory response. Administration of macrolides to reduce autoinducer synthesis might therefore partially prevent the tissue damage.
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ACKNOWLEDGMENTS |
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We gratefully acknowledge B. H. Iglewski for providing plasmids and synthetic autoinducers. This work was supported by a Pfizer grant (to K.T.), a research grant from the Programme Commun de Recherche en Genie Biomedical Geneve-Lausanne 1999-2002 (to C.V.D.), and research grants 3231-051940.97 and 3200-052189.97 from the Swiss National Research Foundation (to C.V.D.).
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Genetics and Microbiology, Medical School of the University of Geneva, CMU, 9 av Champel, CH-1211 Geneva 14, Switzerland. Phone: (4122) 702 56 55. Fax: (4122) 702 57 02. E-mail: Christian.vanDelden{at}medecine.unige.ch.
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Antimicrobial Agents and Chemotherapy, June 2001, p. 1930-1933, Vol. 45, No. 6
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.6.1930-1933.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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