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Antimicrobial Agents and Chemotherapy, December 2000, p. 3441-3443, Vol. 44, No. 12
Department of Molecular and Cell Biology,
University of California, Berkeley, California,1
and Department of Pathology, Microbiology Section,
University of Verona, Verona, Italy2
Received 30 May 2000/Returned for modification 12 July
2000/Accepted 11 September 2000
Immunoblotting with antibody against AcrA, an obligatory component
of the AcrAB multidrug efflux system, showed that this protein was
overexpressed by It is well known that resistance to
fluoroquinolones usually requires alteration in the genes that code for
the targets of these drugs, gyrA and parC
(4-7, 16). On the other hand, it is not clear whether these
mutations alone could produce very high levels of resistance, and
one of the major factors that produce such resistance is sometimes
thought to be an increased drug efflux. This hypothesis has been
examined in several laboratories. Thus, Piddock and associates
(2) examined 36 high-level ciprofloxacin-resistant isolates
of Escherichia coli and found that 22 strains accumulated lower levels of ciprofloxacin than the wild type, in addition to the
gyrA mutations found in all of them. Levy and associates (12) found that 21 of 57 high-level
fluoroquinolone-resistant clinical isolates of E. coli
showed tolerance to cyclohexane, suggesting an elevated broad-spectrum
efflux activity. Furthermore, some of the regulatory factors that may
cause the overproduction of AcrAB, the major, constitutively expressed
multidrug efflux pump of E. coli, were examined: in a 1996 study dealing with 23 fluoroquinolone-resistant E. coli
isolates (9), 3 were shown to produce MarA, a positive
regulator of acrAB transcription (1), constitutively at high levels, and 8 were shown to produce MarA to
higher levels than the wild type upon "induction" with tetracycline or salicylate; and in a 1999 study of 25 fluoroquinolone-resistant, cyclohexane-tolerant strains (13), 9 were shown to have
mutations in marR, the repressor for MarA expression, or in
soxR, the repressor for the expression of SoxS, a close
homolog of MarA. All these studies, however, were somewhat indirect in
view of our knowledge that the AcrAB pump alone contributes in a
decisive manner to the MarA-induced multidrug resistance of E. coli (14). Thus, the identity of the efflux pump
remained unknown in the direct efflux study (2) or in the
solvent resistance study (12), and the examination of
mar and sox systems (9, 13) left open the question of whether other regulatory pathways were altered. We
have therefore examined directly the level of expression of AcrA, one
of the essential components of the AcrAB-TolC multidrug efflux system
(10), by immunoblotting.
The 25 clinical isolates of E. coli, randomly chosen from
the isolates collected during the period of October 1995 through December 1998, were obtained from the Clinical Microbiology Laboratory of the University of Verona Hospital. Each strain was from a different patient. Their ciprofloxacin susceptibilities were tested by the broth
microdilution method in Luria-Bertani broth at 37°C with a standard
inoculum of 104 cells ml
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High-Level Fluoroquinolone-Resistant Clinical
Isolates of Escherichia coli Overproduce Multidrug
Efflux Protein AcrA
ABSTRACT
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170% in 9 of 10 clinical isolates of
Esherichia coli with high-level ciprofloxacin resistance
(MICs, 32 µg/ml) but not in any of the 15 isolates for which the
MIC was 
1 µg/ml.
TEXT
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1. Ciprofloxacin was
obtained from Sigma (St. Louis, Mo.). In terms of susceptibility to
ciprofloxacin, these isolates fell into two groups: one composed of 15 strains containing susceptible strains and moderately resistant strains
(MICs, up to 1.0 µg/ml) and the other composed of 10 strains with
high levels of ciprofloxacin resistance (MICs, 32 µg/ml or higher)
(see Table 1).
TABLE 1.
Ciprofloxacin susceptibilities, QRDR sequences in
topoisomerases, and AcrA expression levels for clinical isolates of
E. coli
We examined the AcrA expression levels of these strains by
immunoblotting, as follows. The strains were grown in Luria-Bertani broth at 37°C until the culture attained a density of about 0.2 mg
(dry weight) ml1 from a previously constructed standard
curve relating the optical density to cell density. These
early-exponential-phase cells were used in order to avoid the problem
of possible induction of AcrAB in the late exponential and stationary
phases (8). The cells were harvested by centrifugation and
were resuspended in the same volume of 1% sodium dodecyl sulfate
(SDS), followed by heating in a boiling water bath for 10 min. The
protein concentrations of the samples were determined by using the
bicinchoninic acid assay (Pierce), and the solutions were adjusted to
the same protein concentration of 2 µg/ml. Identical volumes of the
samples were separated by SDS-slab-polyacrylamide gel electrophoresis
with a 10% acrylamide gel. The proteins were transferred to a
nitrocellulose membrane electrophoretically (4°C, 100 V, 1 h) by
using a 10 mM 3-(cyclohexylamino)-1-propanesulfonic acid buffer (pH 11)
containing 10% methanol. After blocking overnight with 5% dry milk,
the proteins were stained by using anti-AcrA rabbit antibodies
(17) as the first antibody (1 h) and
horseradish-peroxidase-linked anti-rabbit immunoglobulin G (Amersham
Pharmacia) as the second antibody, which was detected with the ECL
Western blotting detection reagent (Amersham Pharmacia) and Kodak
Biomax MR film developed with a Kodak RPX-OMAT processor. The
intensities of the bands obtained were compared by using the analysis
software of ImageMaster VDS (Pharmacia Biotech). Preliminary trials
with the purified AcrA were run to define the range in which the
response was proportional to the amount of the protein applied, and
only data within this range were used. In each experiment, AG100 (a
laboratory strain showing a normal expression level for the AcrAB
system [3, 14]) was included as a standard, and the
AcrA levels in various strains were calculated as relative values in
comparison with that for AG100. Each strain was usually tested at least
twice; the levels found were quite similar; for example, the values for AG102 were 1.76 and 1.81, those for EC44 were 0.94 and 0.96, and those
for EC85 were 1.05 and 1.29.
The results (Table 1) showed clearly that in the susceptible and
low-level-resistant strains there was no significant overexpression of
AcrA (and presumably also of AcrB, which belongs to the same operon),
whereas in all except one of the high-level-resistant strains there was
significant overexpression of AcrA, at levels 170% of that found for
control strain AG100. The sole exception was EC44, for which the MIC
was the lowest among those for this group. Selected strains were
examined for the levels of expression of AcrB by a similar immunoblot
method with anti-AcrB rabbit antibody raised with the purified AcrB
(18). With the AcrB expression level in AG100 taken
as 1.0, the two ciprofloxacin-susceptible isolates
EC104 and EC108 showed expression levels of 0.94 and 0.86, respectively, whereas the high-level-resistant isolates EC107 and EC110
showed expression levels of 2.3 and 2.7, respectively, in perfect
agreement with the expression levels found in these strains for AcrA
(Table 1). Considering that MarA or SoxS was overexpressed in only a
fraction of a similar, highly resistant group of E. coli
isolates (9, 13), our results may suggest that other
regulatory factors, many of which remain to be identified (8), are involved in the elevated levels of expression of
the AcrAB system.
The accumulation of ciprofloxacin was determined by a modification of the method of Piddock and coworkers (2). Thus, the exponential-phase cells were harvested from Luria-Bertani broth by centrifugation, washed and resuspended in 50 mM sodium phosphate buffer (pH 7.0) at an optical density at 600 nm of 1, and incubated with shaking at 37°C. Ciprofloxacin (10 mg/ml) was added, and 1-ml portions were filtered on 0.45-µm-pore-size Millipore filters and washed quickly with 5 ml of 0.1 M LiCl instead of the time-consuming centrifugation steps in the original method. The filter was extracted in 2.5 ml of 0.1 M glycine-HCl buffer (pH 3.0), and the ciprofloxacin was quantitated by fluorescence with a Shimadzu RF 5301 spectrofluorometer. The fluorescence intensity was calibrated by using a 0.01-µg/ml solution of ciprofloxacin in the same buffer. Steady-state accumulation values were calculated by averaging the data for five time points (1, 2, 3, 4, and 5 min); the standard deviation was usually below 10% of the average. In this assay, the two susceptible isolates, isolates EC91 and EC101, accumulated 91 and 109% of the level seen in control strain AG100, respectively. In contrast, all except one of the highly resistant isolates accumulated lower levels of ciprofloxacin than AG100 (average, 72% of the level in AG100), a result confirming that ciprofloxacin was pumped out more effectively in the strains that overexpressed AcrAB. Although EC110, the sole exception, accumulated more ciprofloxacin than AG100, in an earlier series of experiment it accumulated far less, and the reason for the erratic behavior of this strain remains unknown.
The nearly perfect correlation between the high-level resistance to fluoroquinolones and the overexpression of the AcrAB efflux system leads us to the question of whether the very high levels of resistance always require the contribution of efflux. We know that the overexpression of AcrAB alone in AG102 (AG100 marR1) (3), without mutations in topoisomerases, produced only a modest increase in the MIC, to 0.12 µg/ml (Table 1). Fluoroquinolone-resistant isolates of clinical origin do contain an additional mutation(s) in the topoisomerase gene(s). However, Oethinger et al. (11) showed that in a strain containing both a mutation in marR and a mutation in the quinolone resistance-determining region (QRDR) of gyrA, the ofloxacin MIC for E. coli goes up only to 1 µg/ml. Thus, the very high MICs (higher than 32 µg/ml) observed for some strains studied here must involve additional mechanisms, most likely two or more mutations in the target genes (4-7, 16). Indeed, when sequencing of the QRDRs in gyrA and parC was carried out with our high-level-resistant isolates by the procedure described by Everett et al. (2), all of these strains were found to contain two mutations in gyrA and at least one mutation in parC (Table 1). The level of resistance achieved by mutations in the target genes alone cannot be assessed from most studies of laboratory-generated quinolone-resistant strains, which involved successive subculturing in drug-containing media (for example, see references 4 and 11), a procedure that is likely to introduce additionally up-regulation mutations in efflux pumps. However, there are a few studies in which the strains were constructed by the methods of bacterial genetics. Thus, Khodursky et al. (6) showed that the combination of gyrA (S83L) and parC (E84K) mutations (often found among our isolates; see Table 1) produced an apparent norfloxacin MIC of about 25 µg/ml, and Kumagai et al. (7) found that ciprofloxacin MICs for E. coli K-12 strains containing a quinolone resistance mutation in gyrA, in addition to mutations in the QRDR of parC (including ones identical to those observed in this study, such as S80I, S80R, and E84K), were as high as 12.5 µg/ml. These levels of resistance, however, are lower than those found in our isolates with high-level resistance, as exemplified by MICs in the range of 64 to >512 µg/ml (Table 1), suggesting that the very high level ciprofloxacin resistance observed here requires the up-regulation of AcrAB, in addition to multiple changes in the targets.
In order to confirm the participation of the overexpressed AcrAB pump
to the high-level resistance, we transduced the
acrAB::kan mutation into EC114 with phage P1
vir from the strain AG100A, using the procedure described
earlier (14), selecting for kanamycin resistance. The
ciprofloxacin MIC for the resultant transductant, defective in the
AcrAB pump, was 8 µg/ml, strongly decreased from the MIC of 64 µg/ml for strain EC114. This approach by use of transduction was not
possible with the other high-level-resistant strains because they were
already kanamycin resistant. We therefore determined ciprofloxacin MICs
in the presence of an efflux inhibitor, MC 207,110 (purchased from
Sigma as Phe-Arg-naphthylamide) (15), which is reported to
inhibit AcrAB (J. Blais, D. Cho, K. Tangen, C. Ford, A. Lee, O. Lomovskaya, and S. Chamberland, Abstr. 39th Intersci. Conf. Antimicrob.
Agents Chemother., abstr. 1266, 1999). There was a clear decrease
in the MICs for several strains (Table 1). With other strains, however,
the effect of the inhibitor was not apparent. In some cases, this is
possibly because the efflux was caused by systems other than AcrAB or
because mutations in other target genes, such as gyrB or
parE (5), contributed to resistance. In any case,
our study lends support to the idea that increased production of the
AcrAB pump is an important component in the development of high levels
of resistance to fluoroquinolones.
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ACKNOWLEDGMENTS |
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This study was supported in part by a grant from U.S. Public Health Service (grant AI-09644).
A.M. acknowledges the support from the University of Verona, which enabled her visit to University of California.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Molecular and Cell Biology, Room 229 Stanley Hall, University of California, Berkeley, CA 94720-3206. Phone: (510) 642-2027. Fax: (510) 643-9290. E-mail: nhiroshi{at}uclink4.berkeley.edu.
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Antimicrobial Agents and Chemotherapy, December 2000, p. 3441-3443, Vol. 44, No. 12
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