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Antimicrobial Agents and Chemotherapy, July 1999, p. 1681-1685, Vol. 43, No. 7
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Structural Alterations in the Translational
Attenuator of Constitutively Expressed ermC Genes
Christiane
Werckenthin,1
Stefan
Schwarz,1,* and
Henrik
Westh2,3
Institut für Tierzucht und
Tierverhalten der Bundesforschungsanstalt für Landwirtschaft
Braunschweig (FAL), 29223 Celle, Germany,1 and
Department of Clinical Microbiology, Hvidovre Hospital, 2650 Hvidovre,2 and Staphylococcus
Laboratory, Statens Serum Institut, 2300 Copenhagen,3 Denmark
Received 13 October 1998/Returned for modification 28 December
1998/Accepted 4 May 1999
 |
ABSTRACT |
Sequence deletions of 16, 59, and 111 bp as well as a tandem
duplication of 272 bp with respect to the corresponding sequence of
pT48 were identified in the regulatory regions of constitutively expressed ermC genes. Constitutive ermC gene
expression as a consequence of these structural alterations is based on
either the prevention of the formation of mRNA secondary structures in
the translational attenuator or the preferential formation of those
mRNA secondary structures which do not interfere with the translation
of the ermC transcripts. A model for the development of
sequence deletions in the ermC translational attenuator by
homologous recombination is presented and experimentally tested by in
vitro selection of constitutively expressed mutants in staphylococcal
strains deficient and proficient in homologous recombination.
| |
INTRODUCTION |
Macrolide-lincosamide-streptogramin
B (MLS) resistance in staphylococci is mainly based on the
dimethylation of an adenine residue in the 23S rRNA. Among the four
different methylase genes (ermA to -C and
ermF) so far identified in staphylococci (5, 10, 13,
21), the plasmid-encoded gene ermC is most widely distributed in human and animal staphylococci (13). Two
types of ermC gene expression are distinguished: inducible
and constitutive expression (1, 22). Inducible
ermC gene expression via translational attenuation requires
the presence of a functionally intact regulatory region 5' of the
ermC methylase gene (6, 20, 22). This region
consists of an open reading frame (ORF) for a small peptide of 19 amino
acids (aa) and two pairs of inverted repeated sequences 1 to 4 (IR1 to
-4) which are capable of forming several different mRNA secondary
structures (6, 20, 22). Since the ermC-associated ribosomal binding site SD2 and the start codon of the ermC
methylase gene represent part of the IR4, the accessibility of these
structures to ribosomes as a consequence of differential mRNA folding
in the presence or the absence of inducers is essential for the
translation of the ermC transcripts.
In constitutively expressed ermC genes of naturally
occurring staphylococcal plasmids, three different types of mutations in the ermC regulatory region have been identified which
render the IR4 always accessible to ribosomes. These mutations include: deletions of 58 (3), 70 (4), or 107 (9) bp and duplications of 20 to 61 (7, 11, 15,
18) bp, as well as multiple point mutations (16). In
the present study, we describe deletions of 16, 59, and 111 bp as well
as a tandem duplication of 272 bp in the ermC translational
attenuator of naturally occurring staphylococcal plasmids. Moreover, a
model for the development of deletions by homologous recombination is
presented. This model is supported by data obtained from the analysis
of in vitro-selected constitutively expressed ermC
regulatory mutants in recombination-proficient and
recombination-deficient strains.
| |
MATERIALS AND METHODS |
Bacterial isolates and antibiotic resistance testing.
The
four naturally occurring staphylococcal isolates included in this study
were Staphylococcus epidermidis 1193 and the two methicillin-resistant Staphylococcus aureus (MRSA) strains
9940 and 14728 (all from human origin) and Staphylococcus
lentus 29 from a carrier pigeon. Species identification was done
by the ID32 Staph system (BioMérieux, Marcy l'Etoile,
France). Macrolide-lincosamide resistance was determined by the disk
diffusion method. The staphylococcal strains were tested for
constitutivity or inducibility of macrolide-lincosamide resistance by a
modification of the tylosin tartrate test (3).
Molecular techniques.
Plasmid preparation was done according
to a previously described staphylococcus-specific modification of the
alkaline lysis procedure with subsequent purification by affinity
chromatography on Qiagen Midi columns (16). Protoplast
transformation, restriction analysis, agarose gel electrophoresis, and
Southern blotting were performed as previously described (12,
24). The 472-bp HaeIII-HincII internal
fragment of the ermC gene of pE194 was used as an
ermC gene probe in hybridization experiments (8).
The probe was labelled with the nonradioactive ECL (enhanced
chemiluminescence) system (Amersham-Buchler, Braunschweig, Germany).
Hybridization and signal detection were done according to the
manufacturer's recommendations.
To detect novel mutations in the ermC regulatory region, we
used a previously described PCR assay (12). This PCR assay
enables the amplification of the entire regulatory region, including
the 5' end of the ermC gene. An inducibly expressed
ermC gene which carries a complete attenuator yields a PCR
product of 295 bp (12). Plasmids which yielded smaller or
larger amplification products were subjected to sequence analysis. To
determine the type and location of the structural alterations that led
to these different-sized amplification products, the ermC
regulatory region and the 5' end of the ermC structural gene
from plasmids pSES23, pSES25, pSES30, and pSES31, first identified to
carry such mutations, were cloned into pBluescript II SK+ (Stratagene)
by using the single SacI and BclI sites in the
ermC gene area. Sequence analysis by the dideoxy chain
termination method was performed for both strands with the ALF
sequenator (Pharmacia, Freiburg, Germany).
In vitro selection of constitutive mutants.
The
recombination-proficient S. epidermidis strain W69941E
(24), which harbored the 2.3-kbp plasmid pSES28 (23,
24), and the recombination-deficient S. aureus strain
KB103 (2), which harbored plasmid pKB924, a recombinant
plasmid that carried the ermC gene of pE194, were used in
these experiments. The ermC genes of both plasmids pSES28
and pKB924 proved to be expressed inducibly. To select constitutive
mutants, one colony of each of the two test strains was inoculated into
2 ml of brain heart infusion (BHI) broth (Oxoid) and grown under
constant shaking (120 rpm) for 2 h at 37°C. Aliquots of 100 µl
were then plated onto BHI agar plates supplemented with 30 µg of
clindamycin per ml. An aliquot of 100 µl was plated in serial
dilutions on unsupplemented BHI agar to determine the mutation ratio.
Colonies which appeared on the clindamycin-supplemented agar after
24 h at 37°C were tested for constitutive macrolide-lincosamide
resistance. Plasmids of these constitutive mutants were prepared and
checked by PCR (12) for structural alterations in the
ermC regulatory region. At least one representative of each
different-sized amplicon was cloned into pCR-Blunt II-TOPO (Invitrogen,
Leek, The Netherlands) and sequenced.
Nucleotide sequence accession number.
The nucleotide
sequences of the naturally occurring plasmids mentioned in the text
have been submitted to the EMBL database and have been assigned
accession no. Y15273 (pSES25), Y15274 (pSES23), Y17294 (pSES31), and
Y18018 (pSES30).
| |
RESULTS AND DISCUSSION |
Analysis of the ermC regulatory regions of naturally
occurring staphylococci.
During routine screening of
constitutively expressed plasmid-borne ermC genes from
staphylococci of human and animal origin, we detected four novel
structural alterations in the ermC translational attenuator,
as assumed from the sizes of the corresponding amplification products
(Fig. 1). The 2.4-kbp plasmid pSES23 from
S. epidermidis 1193 yielded an amplification product that
was slightly smaller than that of inducibly expressed ermC
genes (Fig. 2). Sequence analysis
confirmed that there was a sequence deletion of 16 bp in the
ermC translational attenuator which comprised the IR3. Since
IR3 plays a crucial role in the induction process as a partner in mRNA
secondary structure formation for either IR2 or IR4, its deletion
renders IR4 always accessible to ribosomes independently of the
presence or the absence of an inducer. The 2.35-kbp plasmid pSES30 from
the MRSA strain 9940 carried a 59-bp deletion which comprised the
entire reading frame for the 19-aa peptide including the IR1 sequence
(Fig. 2). Due to this deletion, the energetically most stable mRNA
secondary structure is formed between IR2 and IR3, rendering IR4
accessible to ribosomes and thus allowing constitutive ermC
gene expression to occur. The 2.3-kbp plasmid pSES25 from S. lentus 29 showed a small amplification product (Fig. 2) which corresponded to a deletion of 111 bp. This deletion comprised almost
the entire translational attenuator (Fig. 2). Of all regulatory elements formerly present, only IR4 remained in plasmid pSES25.
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FIG. 1.
Amplification products obtained from plasmids pSES5 from
S. hominis (carrying a complete attenuator [lane 1])
(12), pSES23 from S. epidermidis (lane 2) (this
study), pSES30 from MRSA (lane 3) (this study), pSES24 from S. epidermidis (carrying a 58-bp deletion [lane 4])
(23), pSES25 from S. lentus (lane 5) (this
study), pSES4a from S. haemolyticus (carrying a 107-bp
deletion [lane 6]) (12), and pSES31 from MRSA (lane 7)
(this study). Lanes M carry the DNA size standard (123-bp ladder;
Gibco-BRL).
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FIG. 2.
Schematic presentation of the ermC regulatory
regions of the inducibly expressed ermC gene of plasmid pT48
(4) and the four plasmids described in this study. SD1 and
SD2 represent the Shine-Dalgarno sequences of the ORF of the 19-aa
peptide and the ermC gene. The arrows indicate IR1 to -4. The truncated ermC gene of plasmid pSES31 is displayed as a
stippled box ( ).
|
|
The 4.3-kbp plasmid pSES31 from MRSA strain 14728 showed two
amplification products upon the PCR analysis (Fig.
2). Moreover,
restriction mapping revealed the presence of two
HaeIII
sites
instead of one in the
ermC structural gene region.
Since one of
the PCR primers used included the
HaeIII site
and the adjacent
sequences, the duplication of this region might
explain the two
amplification products. In fact, sequence analysis
confirmed the
presence of a perfect tandem duplication of 272 bp which
comprised
the final 7 bp of the reading frame of the 19-aa peptide and
the
IR2, IR3, and IR4 sequences, as well as the first 205 bp of the
ermC structural gene. Thus, a complete translational
attenuator
as seen in the inducibly expressed genes preceded a
truncated
ermC gene which was followed by an incomplete
attenuator that
preceded a complete
ermC gene (Fig.
2).
Since the reading frame
for the 19-aa peptide including IR1 was missing
in the regulatory
region 5' of the complete
ermC gene, this
large tandem duplication
finally had the same effect on
ermC
gene expression as the 59-bp
deletion detected in plasmid
pSES30.
A model for the development of deletions by homologous
recombination.
All tandem duplications in the ermC
translational attenuator of naturally occurring plasmids (Table
1) reported so far represent unique
structural alterations which may have occurred by either replication
slippage or illegitimate recombination. In contrast, most sequence
deletions described in the ermC translational attenuator have been detected in several plasmids from epidemiologically unrelated
staphylococci (Table 1), suggesting the presence of a common mechanism.
Homologous recombination between different parts of the regulatory
region might provide an explanation for the occurrence of identical or
very closely related mutations in the ermC translational
attenuators of plasmids from epidemiologically unrelated staphylococci.
Assuming that the deleted attenuators have developed from complete
attenuators as described to be present in plasmid pT48 (4),
pE194 (8), or pSES5 (12), analysis of the regions
upstream and downstream of the 16-, 59-, and 111-bp deletions revealed
the presence of stretches of 9 to 13 bp with 78 to 85% sequence
identity (Fig. 3). These possible sites
for homologous recombination show a characteristic arrangement:
identity at both ends and two mismatches in the central area. Similar
arrangements were also seen in the regions upstream and downstream of
the previously described 58-, 70-, and 107-bp deletions (Fig. 3). When
thinking of suitable sequences for homologous recombination in the
ermC translational attenuator, one may consider IR1 and IR3,
but also IR2 and IR4, as most promising partners. However, if
recombination between these pairs of sequences occurs, the resulting
mutants cannot be detected by screening for macrolide resistance. A
recombination between IR1 and IR3 will first bury the SD2 sequence and
the start codon of the ermC gene in the secondary structure
formed by IR3 and IR4. When this mRNA secondary structure is destroyed
by a stalled ribosome at codon 9 in the leader peptide, the stalled ribosome will sterically inhibit binding of a ribosome to the SD2
sequence and so prevent translation of the ermC transcripts. A recombination between IR2 and IR4 will delete most of the SD2 sequence and thus inhibit ermC gene expression.
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TABLE 1.
Structural alterations in the translational attenuators
of naturally occurring ermC-carrying plasmids from human and
animal sources
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FIG. 3.
Possible sites for homologous recombination in the
ermC translational attenuators of plasmids pSES23, pA22,
pSES30, pJ74, pNE131, and pSES25 leading to deletions of 16, 58, 59, 70, 107, or 111 bp shown on the noncoding strand. The sequences
determined in the respective translational attenuators are displayed in
boldface capital letters. The lowercase letters represent the beginning
and end of the deleted sequences. Important structural elements with
respect to Fig. 2, such as the Shine-Dalgarno sequences SD1 and SD2, as
well as part of the IR2 sequence, are indicated below or above the
corresponding sequences. Vertical bars mark identical bases in the
sequences involved in the recombinational events.
|
|
To provide experimental support for the recombination hypothesis,
constitutive mutants were selected by growth of the two
inducibly
resistant strains in the presence of the noninducer
clindamycin.
Despite the fact that mutation to constitutive
ermC gene
expression was less than 1 × 10
7 in both strains,
the recombination-proficient strain
S. epidermidis W69941E
yielded about six times as many constitutive mutants as
the
recombination-deficient strain
S. aureus KB103 did. PCR
analysis
of the
ermC regulatory region of the 31 constitutive mutants obtained
from
S. epidermidis W69941E
revealed the presence of five different-sized
amplicons, all of which
were associated with sequence deletions.
Sequence deletions of 16, 58, and 111 bp, seen in nine, seven,
and another seven mutants,
respectively, corresponded exactly
to those mutations seen among the
naturally occurring plasmids.
A fourth sequence deletion of 120 bp,
which occurred in five mutants,
comprised the entire regulatory region
and may be due to a recombination
between SD1 and SD2 as well as the
start codons of the reading
frame of the 19-aa peptide and that of the
ermC methylase gene.
So far, such a deletion has not been
detected in naturally occurring
plasmids. The fifth structural
variation seen in the remaining
three constitutively expressed mutants
included the insertion
of a T at position 13 in the reading frame of
the 19-aa peptide,
which changed the fifth codon (AGT) into a
translational stop
codon (TAG). Three base pairs downstream of this
stop codon, a
93-bp deletion was detected which ended at the
ermC-associated
ribosomal binding site. Such a structural
alteration has also
not been observed in naturally occurring plasmids
and cannot be
explained by the one-step recombination
model.
In contrast to the different mutations seen in the
recombination-proficient strain, we obtained only five constitutive
mutants
from experiments carried out in parallel with the
recombination-deficient
strain. All five mutated plasmids yielded PCR
fragments which
were indistinguishable in their sizes from one another
and from
that obtained from the original inducibly expressed plasmid
pKB924.
Sequence analysis showed that all five mutant plasmids carried
the same mutation, namely the exchange of T with C at position
7 in the
IR3 sequence of the
ermC gene of pKB924. This 1-bp exchange
strongly destabilized the formation of a mRNA secondary structure
between IR3 and IR4. The free energy of pairing was calculated
(
19) to be
G =
12.2 kcal (ca.
51.0
kJ)/mol for IR3-IR4 in
the original pKB924 and only
G =
6.6 kcal (ca.
27.6 kJ)/mol
for IR3-IR4 in the constitutive
mutant of pKB924. This decrease
in stability is likely to explain
constitutivity.
The data obtained from this study showed that the recombination system
of the host cell obviously plays a role in the development
of the
different types of structural alterations associated with
constitutive
ermC gene expression. Assuming that most naturally
occurring
staphylococci are recombination proficient, it is not
surprising to
find identical or closely related deletions in the
ermC
translational attenuators of naturally occurring staphylococcal
plasmids and in those from in vitro-selected mutants in a
recombination-proficient
strain. Bearing in mind the widespread
occurrence of
ermC-carrying
plasmids among staphylococci
from humans and animals and the observation
that constitutive mutants
can be generated in vitro after overnight
cultivation in the presence
of noninducers, a prudent use of noninducers,
such as 16-membered
macrolides, lincosamides, and streptogramins,
is strongly
recommended.
| |
ACKNOWLEDGMENTS |
We thank Kenneth W. Bayles, Department of Microbiology, Molecular
Biology, and Biochemistry, University of Idaho, for providing S. aureus KB103, as well as Keith G. H. Dyke, Microbiology Unit, Department of Biochemistry, University of Oxford, Oxford, United Kingdom, for helpful discussions.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Institut
für Tierzucht und Tierverhalten der Bundesforschungsanstalt
für Landwirtschaft Braunschweig (FAL), Dörnbergstr. 25-27, 29223 Celle, Germany. Phone: (49) 5141-384673/77. Fax: (49)
5141-381849. E-mail: SCHWARZ{at}KTF.FAL.DE.
| |
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Antimicrobial Agents and Chemotherapy, July 1999, p. 1681-1685, Vol. 43, No. 7
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
