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Antimicrobial Agents and Chemotherapy, October 1998, p. 2590-2594, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Characterization of Mutations in the
rpoB Gene That Confer Rifampin Resistance in
Staphylococcus aureus
Hélène
Aubry-Damon,1,2
Claude-James
Soussy,2 and
Patrice
Courvalin1,*
Unité des Agents Antibactériens,
Institut Pasteur, 75724 Paris Cedex 15,1 and
Service de Bactériologie-Virologie-Hygiène,
Hôpital Henri Mondor, 94010 Créteil,2 France
Received 9 March 1998/Returned for modification 10 June
1998/Accepted 8 July 1998
 |
ABSTRACT |
Mutations in the rifampin resistance-determining (Rif) regions of
the rpoB gene of Staphylococcus aureus mutants
obtained during therapy or in vitro were analyzed by gene amplification and sequencing. Each of the resistant clinical isolates, including five
nonrelated clones and two strains isolated from the same patient, and
of the 10 in vitro mutants had a single base pair change that
resulted in an amino acid substitution in the 
subunit of RNA polymerase. Eight mutational changes at seven positions were
found in cluster I of the central Rif region. Certain
substitutions (His481/Tyr and Asp471/Tyr [S. aureus
coordinates]) were present in several mutants. Substitutions
Gln468/Arg, His481/Tyr, and Arg484/His, which conferred high-level
rifampin resistance, were identical or in the same codon as those
described in other bacterial genera, whereas Asp550/Gly has not been
reported previously. Substitutions at codon 477 conferred high- or
low-level resistance, depending on the nature of the new amino
acid. The levels of resistance of in vivo and one-step in vitro mutants
carrying identical mutations were similar, suggesting that no
other resistance mechanism was present in the clinical
isolates. On the basis of these data and the population
distribution of more than 4,000 clinical S. aureus isolates, we propose 
0.5 and 
8 µg/ml as new breakpoints for the
clinical categorization of this species relative to rifampin.
| |
INTRODUCTION |
Staphylococcus is
the bacterial genus most frequently responsible for
infections of prosthetic devices, osteomyelitis, and endocarditis
(11, 15, 23). During the last 10 years, the proportion of
methicillin-resistant Staphylococcus aureus (MRSA) isolates
in hospitals has reached nearly 29% in the United States (19) and 40% in Europe (27). Most MRSA isolates
are resistant to multiple antibiotics (4, 16) and more
than 50% are resistant to rifampin, whereas 1% of
methicillin-susceptible S. aureus (MSSA) isolates are
resistant to rifampin (27). Vancomycin is the therapy of
choice against S. aureus when -lactams are
inappropriate. However, because of poor tissue diffusion and
moderate bactericidal activity (2), vancomycin is often
combined with rifampin for deep-seated infections (6,
10). Fluoroquinolones in association with rifampin also
represent an alternative strategy for the prevention of the
emergence of resistant mutants in the treatment of serious MSSA infections (7).
Rifampin acts by interacting specifically with the subunit of the
bacterial RNA polymerase encoded by the rpoB gene
(1). Rifampin resistance in Escherichia coli
(13, 22) and S. aureus is due to alterations
in the target leading to a reduced affinity of the enzyme for the
antibiotic (17). Alignment of the predicted amino acid
sequence of the S. aureus RNA polymerase subunit with those of other bacterial genera identified conserved domains in
all the sequences (1). One of them, between amino acids 486 and 717 (E. coli coordinates), includes the loci
responsible for rifampin resistance in E. coli
(13), Mycobacterium tuberculosis (24),
Streptococcus pneumoniae (9), and
Neisseria meningitidis (5). We have thus
amplified and sequenced portions of rpoB from
rifampin-susceptible and -resistant S. aureus isolates
from the same patient. These portions correspond to the mutated regions in rifampin-resistant mutants of the previously studied bacterial genera. Mutants obtained in vitro were also studied. Attempts to
correlate the various levels of rifampin resistance and the position of the rpoB mutations were made.
| |
MATERIALS AND METHODS |
Bacterial strains.
Rifampin-susceptible and -resistant
matched clinical strains of MSSA (three pairs and three strains from
the same patient) or MRSA (two pairs) were used in the study. Each pair
and the three strains from the same patient were isolated between 1992 and 1997 before and during therapy with rifampin either alone or in
combination (Table 1). Plasmid-free
S. aureus RN4220, which was susceptible to antibiotics,
was used for the in vitro selection of rifampin-resistant mutants
(14).
Isolation of rifampin-resistant mutants of S. aureus RN4220 and of clinical isolate MSSA BM4368.
Approximately 108 CFU of exponentially growing bacteria was
plated onto Mueller-Hinton agar (Sanofi Diagnostics Pasteur,
Marnes-la-Coquette, France) containing concentrations of rifampin
(provided by Merrell-Dow Research, Milan, Italy) of 0.016 to 64 µg/ml. After 24 h of incubation at 37°C, the numbers of
colonies on agar with rifampin concentrations of 0.032 µg/ml were
counted and the mutation frequencies were determined relative to the
total count of viable organisms plated.
Antibiotic susceptibility testing.
S. aureus
strains were screened for rifampin resistance by the disk-agar
diffusion method (Sanofi Diagnostics Pasteur), and resistance was
confirmed by determination of the MICs by dilution in Mueller-Hinton
agar (18) with an inoculum of 104 CFU per spot.
Analysis of total DNA by pulsed-field gel electrophoresis.
Contour-clamped homogeneous electric field electrophoresis of
SmaI restriction endonuclease (United States Biochemicals,
Cleveland, Ohio) digests of genomic DNA was performed with a CHEF-DR II
system (Bio-Rad Laboratories, Nazareth, Belgium) as described
previously (3). Strains were assigned to the same
macrorestriction genotype when they shared electrophoretic
restriction patterns that differed by three or fewer fragments
(26) and displayed a coefficient of similarity (CS) equal to
or greater than 0.85 (8). The CS was calculated as follows:
CS = 2 × number of matching bands/total number of bands in
both strains.
Detection of mutations in the rpoB gene.
Total
DNA from S. aureus was purified (29) and was
used as a template for amplification by PCR. Two portions of the
rpoB gene from S. aureus were amplified: a
702-bp fragment from nucleotide positions 441 to 673 (S. aureus coordinates) corresponding to the so-called rifampin
resistance-determining (Rif) region in the center of the E. coli
rpoB gene (13) and a 158-bp fragment from nucleotide
positions 94 to 144 in which a substitution (Val143/Phe) conferring
rifampin resistance has also been reported in E. coli (22). The 20-mer oligodeoxyribonucleotides used as primers
were F3 (5'-AGTCTATCACACCTCAACAA) and F4
(5'-TAATAGCCGCACCAGAATCA) for the larger fragment and D1
(5'-GTGTAAAAGTGCGTCTAATC) and D2 (5'-ATAAACGGATGGTGAACGAA) for the smaller fragment.
Amplification was carried out in a 100-µl volume containing 40 pmol
of each oligonucleotide primer, each 2'-deoxynucleoside 5'-triphosphate at a concentration of 100 mM, reaction buffer (United States
Biochemicals), 2 µl of a template DNA sample containing 100 ng of
DNA, and 1 U of Taq DNA polymerase (United States
Biochemicals). The reactions were performed in a DNA thermal cycler
(Perkin-Elmer Cetus, Norwalk, Conn.) for 35 cycles. The conditions were
4 min at 94°C for denaturation, 3 min at 54°C for preannealing,
45 s at 52°C for annealing, and 45 s at 72°C for
polymerization for the 702-bp fragment. The PCR conditions for the
158-bp fragment differed by the lack of preannealing and by the use of
an annealing temperature of 55°C. The amplification products were
purified on Microspin S-400 HR columns (Pharmacia LKB Biotechnology,
Uppsala, Sweden), cloned into pCRII vector (Original TA Cloning Kit;
Invitrogen), and sequenced by the dideoxy chain termination method
(20) with T7 DNA polymerase (T7 Sequencing kit; Pharmacia)
and [
-35S]dATP (Amersham Radiochemical Center,
Amersham, England).
| |
RESULTS AND DISCUSSION |
Population distribution of S. aureus.
The MICs of
rifampin for 4,644 clinical S. aureus strains isolated
at Hopital Henri Mondor between 1993 and 1996 are presented in Fig.
1. On the basis of this multimodal
distribution, the strains were categorized into categories of
susceptible (MICs, 0.5 µg/ml), low-level resistant (MICs, 1 to 4 µg/ml), and high-level resistant (MICs, 8 µg/ml) according to the
indicated breakpoints.
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FIG. 1.
Distribution of rifampin MICs for 4,644 S. aureus strains isolated at Henri Mondor Hospital between 1993 and
1996.
|
|
Typing of clinical isolates.
The members of each of the five
pairs and of the three isolates from the same patient had similar
resistance phenotypes except for that for rifampin (Table 1).
Pulsed-field gel electrophoresis of total DNA digested with
SmaI is suitable for discrimination of S. aureus clones (25). The two members of each pair and
the three strains from the same patient had indistinguishable DNA profiles (data not shown), indicating that the resistant mutants were
selected in vivo under therapy with rifampin. The five pairs of
clinical strains and the three isolates from the same patient displayed
six SmaI patterns (CS range, 0.5 to 0.7) and were therefore not clonally related.
Selection of rifampin-resistant mutants.
Rifampin-resistant mutants were obtained at frequencies of
10
7 to 108 by plating S. aureus RN4220 (MIC, 0.008 µg/ml) and clinical isolate MSSA
BM4368 (MIC, 0.016 µg/ml) onto solid medium containing rifampin at
various concentrations. The mutation frequencies to low- and high-level
rifampin resistance were similar and were not affected by the
concentration of the selecting agent, which was less than 2 µg/ml.
This result suggests that resistance to high levels of rifampin does
not arise by sequential independent events but, rather, arises in a
single-step fashion. The relative ease with which rifampin-resistant
S. aureus mutants were obtained confirms that this
antibiotic must not be prescribed alone and that considerable attention
must be paid to interactions between rifampin and other antimicrobial agents. In fact, rifampin-resistant S. aureus BM4627 and BM4364-R mutants emerged in vivo under
combination therapy. Ten mutants of S. aureus RN4220
obtained in vitro in two independent experiments were selected for
further studies.
DNA sequence analysis and susceptibility to rifampin.
The
sequences of the rpoB Rif gene region from nucleotides 441 to 673 (S. aureus coordinates) of seven
high-level-resistant clinical isolates and of their susceptible
counterparts, two in vitro low-level-resistant mutants
(RN4220-R1 and RN4220-R2), and eight
high-level-resistant mutants were determined (Fig.
2). Relative to their susceptible
counterparts, the 17 in vitro and in vivo mutants had a single base
pair change in the Rif region of the rpoB gene that resulted
in an amino acid substitution, although the occurrence of other
mutations in nonsequenced regions of the rpoB gene cannot be
excluded. Eight mutational changes were found at seven positions: six
clustered from nucleotide positions 464 to 484 and one was at position
550 (Table 2). The mutations in the
E. coli rpoB gene involved in rifampin resistance can be
assigned to three clusters, clusters I, II, and III (13).
Since no strain had mutations in clusters II and III, we do not know if
these regions are involved in rifampin resistance in S. aureus, as has been described for high- and low-level (cluster II)
or very low level (cluster III) resistance in M. tuberculosis (24) and E. coli
(13) (Fig. 2). Replacement of aspartate 550 by a glycine was
a new substitution found outside the clusters at a position where
E. coli and M. tuberculosis have a threonine and
a valine, respectively.
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FIG. 2.
Amino acid sequence comparison of the Rif regions of
E. coli (Ec) and S. aureus (Sa). Clusters I,
II, and III are indicated by dashed lines. Identical amino acids are
indicated by asterisks, and gaps are indicated by dashes. Positions
known to be involved in rifampin resistance in E. coli are
indicated by downward-pointing arrows (mutations) or triangles
(insertions) or are underlined (deletions). Mutations leading to low-
and high-level rifampin resistance in S. aureus are
indicated by single and double upward-pointing arrows, respectively.
|
|
Certain mutations in cluster I were frequently found: the His481/Tyr
substitution occurred in two clinical isolates and in
four
high-level-resistant mutants obtained independently in vitro;
the
Asp471/Tyr substitution was present in two in vivo
low-level-resistant
mutants, BM4368-R
2 and BM4367-R,
and in the in vitro low-level-resistant
mutant
RN4220-R
2. The MICs of rifampin for mutants that were
obtained
in vivo and in vitro and that had identical mutations were
similar
and were within 1 dilution, suggesting that reduced affinity of
the enzyme for the antibiotic following the occurrence of a mutation
in
the Rif region of the
rpoB gene is the major mechanism of
resistance
in
S. aureus.
Comparative analysis of the level of resistance to rifampin in
S. aureus and of the mutation sites indicated that
high-level
resistance correlated with mutations at codons 468 and
481 and
that low-level resistance was associated with a mutation
at codon
471 (
S. aureus coordinates). These
codons correspond to those
associated with respective similar
levels of resistance in
E. coli (
13),
N. meningitidis (
5),
M. tuberculosis
(
24), and
Mycobacterium leprae
(
12). However, replacement of alanine at
position 477 by a
valine led to low-level resistance (mutant
RN4220-R
1),
and replacement of alamine at position
477 by an aspartate led
to high-level resistance (mutants
RN4220-R
3 and BM4368-R
1). This
is not
surprising since alanine and valine are both hydrophobic
amino acids,
whereas aspartate is acidic. It thus appears that
the level of rifampin
resistance in
S. aureus depends not only
on the
position of the mutation but also on the nature of the
new amino acid.
Relative to the corresponding susceptible strain, BM4368, resistant
clinical isolates BM4368-R
1, selected under rifampin
therapy
(1,800 mg per day), and BM4368-R
2, obtained 3 days
after the end
of the treatment, had single base pair changes that
resulted in
a different level of rifampin resistance. They shared the
same
mutation as in vitro low-level-resistant mutant
RN4220-R
2 and
high-level-resistant mutant
RN4220-R
3, respectively (Table
2).
The low- and
high-level-resistant mutants characterized in the
present study are
adequately categorized by using the breakpoints
based on the population
distribution of a large number of clinical
isolates (Fig.
1).
Mutations at positions 468 and 481 led to resistance to very high
concentrations of rifampin and might point to amino acid
changes in the
subunit that prevent the binding of rifampin
to RNA polymerase.
Indeed, it has been shown in
E. coli that residues
516 to
540 (positions 471 to 495 in Rif region cluster I;
S. aureus coordinates) are part of the target of rifampin
(
28) and participate,
along with residues 1065 and 1237 (
E. coli coordinates), in the
formation of the
initiation site when the
subunit is assembled
in the RNA polymerase
complex (
21).
We also sequenced the
rpoB region, from codons 94 to
144, which corresponds to the region containing a Rif mutation
(Val146/Phe)
in
E. coli (
22). None of the 17
S. aureus mutants examined in
the present study had
substitutions in their N-terminal cluster,
which is distant, by almost
400 amino acids, from the central
Rif region. This mutation, not
detected in subsequent studies,
is probably rare but suggests
that the amino acid residue at position
146 and the central Rif
region might jointly form the rifampin
binding site (
21).
In conclusion, using gene amplification and sequencing, we have
established that rifampin resistance in
S. aureus is
probably
due to mutations in the Rif region of the
rpoB gene
and that the
resistance levels are dependent on both the location and
the nature
of the amino acid substitution. With one exception, the
resistance
mutations detected in
S. aureus were
identical to or were in the
same codon as those in other
eubacteria, confirming that the regions
implicated in the interaction
with rifampin are conserved among
procaryotes.
| |
ACKNOWLEDGMENTS |
We thank R. Leclercq for having incited us to initiate this study
and B. Périchon and G. Gerbaud for constant technical advice to
H. Aubry-Damon.
This work was supported in part by a Bristol-Myers Squibb Unrestricted
Biomedical Research Grant in Infectious Diseases.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Unité des
Agents Antibactériens, Institut Pasteur, 28, rue du Docteur Roux,
75724 Paris Cedex 15, France. Phone: (33) (1) 45 68 83 20. Fax: (33) (1) 45 68 83 19. E-mail: pcourval{at}pasteur.fr.
| |
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Antimicrobial Agents and Chemotherapy, October 1998, p. 2590-2594, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
