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Antimicrobial Agents and Chemotherapy, June 1998, p. 1392-1396, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
A New Ketolide, HMR 3004, Active against
Streptococci Inducibly Resistant to Erythromycin
Adriana
Rosato,1
Hubert
Vicarini,1
Alain
Bonnefoy,2
Jean-François
Chantot,2 and
Roland
Leclercq1,*
Service de Bactériologie-Virologie,
Hôpital Henri Mondor-Université Paris XII,
Créteil,1 and
Hoechst-Marion-Roussel, Romainville,2
France
Received 8 December 1997/Returned for modification 13 February
1998/Accepted 24 March 1998
 |
ABSTRACT |
HMR 3004 is a new hydrazono ketolide characterized by a 3-keto
function instead of the cladinose moiety. The effect of this antimicrobial agent on inducible and constitutive
macrolide-lincosamide-streptogramin B (MLSB) resistance was
tested in a lacZ reporter system under control of several
ermAM-like attenuator variants. For one constitutively resistant Streptococcus agalactiae strain, three inducibly
resistant Streptococcus pneumoniae strains, and one
inducibly resistant Enterococcus faecalis strain, the
attenuators fused with lacZ were cloned into the shuttle
plasmid pJIM2246 and the plasmid was introduced into
Staphylococcus aureus RN4220. For the wild-type attenuators, HMR 3004 was a very weak inducer, unlike its cladinose counterpart RU 6652 and erythromycin. As expected, for the fusion originating from the constitutively resistant S. agalactiae
strain, the level of uninduced 
-galactosidase synthesis was high.
For one S. pneumoniae attenuator, mutations in the 3' end
of the attenuator that weakened the stem-loop structure that sequesters
the ribosome-binding site and start codon for ermAM
methylase could explain the high level of uninduced -galactosidase
produced. For streptococci, the activity of HMR 3004 correlated with
the basal level of -galactosidase synthesized. The weak inducer
activity of HMR 3004 explained its activity against inducibly
MLSB-resistant S. pneumoniae but did not
correlate with the moderate activity of the antibiotic against inducibly resistant E. faecalis.
| |
INTRODUCTION |
The emergence of resistance to
erythromycin in enterococci, staphylococci, pneumococci, and other
streptococci is reported worldwide (28). Modification of the
ribosomal target of the macrolides remains a frequent mechanism of
resistance, although active efflux of erythromycin, recently reported
in Streptococcus pyogenes and Streptococcus
pneumoniae, appears increasingly prevalent (7, 26, 27).
N-6 dimethylation of a specific adenine residue in 23S rRNA confers
cross-resistance to macrolides, lincosamides, and streptogramins, the
so-called MLSB phenotype (16). MLSB resistance is encoded by the prototype ermAM gene from
plasmid pAM77 in Streptococcus sanguis (17).
Hybridization experiments and nucleotide sequencing have shown that
determinants closely related to the ermAM gene are
widespread in streptococci, pneumococci, and enterococci, in which they
are borne by transposons similar to Tn1545 (22,
30) or Tn917 (29) or by plasmids
(15). Expression of MLSB resistance may be
inducible or constitutive, depending upon a putative regulatory region
preceding the ermAM gene. This region is composed, from
5' to 3', of sequences coding for a putative 36-amino-acid leader
peptide followed by a set of inverted repeats forming 14 possible axes
of symmetry (17). Since this structure resembles one,
preceding the ermC gene, that is responsible for
translational attenuation of MLSB resistance in
Staphylococcus aureus, a similar mechanism has been proposed for the expression of the ermAM gene (17,
33). In this model, the ribosome-binding site and the start codon
for the methylase are sequestered within a stem-loop structure and are
therefore inaccessible to the ribosomes, thus preventing methylase
synthesis. It has been proposed that erythromycin provokes the stalling
of ribosomes while the leader peptide is translated. Stalling, in turn,
disrupts the secondary structure which sequester the initiation sequences for the methylase. Phenotypic expression of inducible MLSB resistance differs between streptococci and
staphylococci. In staphylococci, inducible resistance is dissociated
between erythromycin or other commercially available 14- and
15-membered macrolides, which are inducers, and 16-membered macrolides
and lincosamides (e.g., clindamycin), which are not (19,
32). By contrast, there is cross-resistance between
MLSB antibiotics, which are efficient inducers in
streptococci (11, 17).
Several macrolides derived from erythromycin, such as clarithromycin,
dirithromycin, and azithromycin, have recently been introduced in
therapy. Although these antimicrobial agents display significantly
improved pharmacokinetic properties, they do not overcome
MLSB resistance (1). Recently, a new class of
macrolides with 14-membered lactone rings, the ketolides, which are
derivatives of erythromycin A characterized by a 3-keto function
instead of the cladinose moiety, has been shown to be active against
most erythromycin-resistant gram-positive organisms (2, 3,
10). One of the most active ketolides is HMR 3004, which is a
hydrazono ketolide (2). In recent studies, this
antimicrobial agent demonstrated activity against most streptococci and
pneumococci cross-resistant to erythromycin, spiramycin (a 16-membered
macrolide), and clindamycin (2, 3, 10). This activity was
attributed to the lack of induction of resistance to MLSB
by this compound (3). In the investigation described in this
report, we have compared the ability of HMR 3004 to induce
-galactosidase activity to those of its cladinose counterpart, RU
66252, and of erythromycin in ermAM-lacZ gene fusions
from strains for which the MICs of HMR 3004 varied.
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MATERIALS AND METHODS |
Bacterial strains.
The activity of HMR 3004 was tested
against 40 clinical isolates of streptococci and enterococci including
11 Enterococcus faecalis, 2 Enterococcus faecium,
14 S. pneumoniae, 6 oral streptococcal and 7 Streptococcus agalactiae isolates resistant to erythromycin and lincomycin (31). The strains were isolated from patients hospitalized in various hospitals in Europe and the United States at
different times, and no link could be established between the patients,
whose infections were considered epidemiologically unrelated. The
erythromycin-susceptible strains E. faecalis JH2-2
(18), S. agalactiae HM50, and S. pneumoniae HM51 (31) and strain E. faecalis
JH2-2/pAM1, which was constitutively resistant to erythromycin (20), were used as controls.
Antibiotic susceptibility testing.
The MICs of the
antibiotics were determined by the agar dilution method with
Mueller-Hinton medium (Sanofi Diagnostics Pasteur, Marnes-la-Coquette,
France) supplemented with 5% horse blood and an inoculum of
104 cells per spot (8). The plates were
incubated for 24 h at 37°C in 5% CO2. The following
antibiotics were provided by their manufacturers: erythromycin,
chloramphenicol, HMR 3004, and RU 66252 (Hoechst-Marion-Roussel,
Romainville, France), spiramycin (Rhône-Poulenc, Rorer, Antony,
France), and lincomycin (Upjohn Laboratories, Val de Reuil, France). RU
66252 is structurally similar to HMR 3004 except for a substitution of
the 3-keto function by a cladinose sugar.
Gene fusions.
The regulatory regions and the first 24 nucleotides of the ermAM-like genes of four inducible
strains (S. pneumoniae HM30, HM34, and HM28 and E. faecalis HM3) and of a constitutive strain (S. agalactiae HM1081) were amplified by PCR with oligonucleotides SR3
(5'-CTTAGAAGCAAACTTAAGAGTGTGT-3') and SR5
(5'-GGTTGAGTACCTTTTCATTCGTTAA-3'), which are primers
intended to amplify the regulatory regions of most
ermAM-related genes on the basis of sequence
comparison. The amplification products were purified and sequenced by
the dideoxy chain termination technique (24). The PCR
products were treated with T4 DNA polymerase to create blunt
extremities and were cloned into the SmaI site of the fusion
vector pMC1871 (which encodes tetracycline resistance) (Pharmacia
Biotech, Saint Quentin-en-Yvelines, France) which contains a
promoterless lacZ gene. The constructs were introduced by
transformation into Escherichia coli MC1061 (9),
and the transformants were plated onto media containing 10 µg of
tetracycline per ml. The colonies were screened for -galactosidase activity in brain heart infusion agar (bioMérieux, La Balme les Grottes, France) containing an inducing concentration of erythromycin (25 µg/ml) and -D-galactopyranoside. For each strain,
the recombinant plasmid was purified from one of the clones producing
-galactosidase in the presence of erythromycin. The recombinant
plasmids were digested with PstI, and the fused
ermAM-lacZ fragments were subcloned in the shuttle
vector pJIM2246, which confers resistance to chloramphenicol (23), and were introduced by transformation into E. coli MC1061. The hybrid plasmids were purified and introduced by
electroporation into S. aureus RN4220. Total and plasmid
DNAs were isolated from E. coli by using commercial kits
(Qiagen kit; Qiagen, Courtabeuf, France) and from S. aureus
as described previously (13).
-Galactosidase induction assays.
Staphylococci were grown
to an optical density of 0.8 at 600 nm in brain heart infusion broth
containing chloramphenicol (25 µg/ml). Cultures not induced or
induced with nearly one-fifth of the MIC of a macrolide (0.03 µg of
erythromycin or RU 66252 per ml and 0.005 µg of HMR 3004 per ml) were
washed and lysed by sonication in TDTT (Tris-HCl 50 mM [pH 7.8],
dithiothreitol 20 mM), and the cell debris was removed by
centrifugation at 20,000 × g for 10 min. The protein
concentration in the supernatants (S20) was determined by the
technique of Bradford (5). -Galactosidase activity was
assessed as described previously (21). The chloramphenicol acetylase activities of the S20 extracts of induced and noninduced cells were measured as a control (25).
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RESULTS |
Activity of HMR 3004 against streptococci and enterococci.
The
40 streptococci and enterococci studied were resistant to erythromycin
(MICs, 16 to 8,000 µg/ml) (Table 1).
Expression of MLSB resistance in these strains was
previously characterized by microbiological techniques and was found to
be inducible in 24 strains of streptococci and 11 strains of
enterococci and constitutive in five strains (2 E. faecalis,
1 S. agalactiae HM1081, and 2 S. pneumoniae
strains) (31). The MICs of HMR 3004 were dispersed and
ranged from <0.016 to 4 µg/ml for streptococci and from 2 to greater
than 32 µg/ml for enterococci (Table 1). However, the activity of HMR
3004 differed depending on the inducible or constitutive expression of
MLSB resistance. The MICs of HMR 3004 for 21 pneumococci
and streptococci inducibly resistant to erythromycin were less than or
equal to 0.25 µg/ml, as was true for the susceptible control strains
(Table 1) and for previously reported erythromycin-susceptible strains
(2, 3, 10); this was not true for three strains, however,
including S. pneumoniae HM30 (MICs, 0.5 to 2 µg/ml). By
contrast, the activity of HMR 3004 against enterococci inducibly resistant to MLSB antibiotics was markedly diminished in
comparison to that against the erythromycin-susceptible control strain
(Table 1). After induction with 0.1 µg of erythromycin per ml, the
MICs of HMR 3004 for streptococci with inducible MLSB
resistance increased from 0.03 to 2 µg/ml to 0.12 to 32 µg/ml and
MICs of inducible enterococci increased from 2 to 16 µg/ml to 16 to
32 µg/ml (Table 1).
HMR 3004 was much less active against the six constitutively resistant
strains (MICs, 4 to 
32 µg/ml), including the control strain
E. faecalis JH2-2/pAM1, although it was still
considerably more active than erythromycin. As expected, the MICs of
the ketolide did not further increase after culture in the presence of
erythromycin (Table 1).
Gene fusion studies.
The abilities of erythromycin, HMR 3004, and RU 66252 to induce the synthesis of -galactosidase were studied
against four strains with inducible MLSB resistance
(S. pneumoniae HM28, HM30, and HM34 and E. faecalis HM3) and one strain with constitutive MLSB resistance (S. agalactiae HM1081) in
fusion experiments. The MICs of erythromycin, HMR 3004, and RU 66252 are presented in Table 2. HMR 3004 was poorly active against the inducibly resistant strains S. pneumoniae HM30 and E. faecalis HM3.
The sequence upstream from the
ermAM-related genes was
amplified by using SR3 and SR5 oligodeoxynucleotides as
primers and
total DNA from the five strains as a template. The
inducibly resistant
strains yielded a ca. 380-bp fragment,
whereas the constitutively
resistant strain
S. agalactiae HM1081 yielded a 170-bp PCR product.
The sequences of
the PCR products and of the corresponding portion
of
ermAM from pAM77 are presented in Fig.
1.
Alignment of the
sequence of
S. agalactiae HM1081 with that
of the 5' end of the
ermAM gene from plasmid pAM77
revealed within the regulatory region
a large deletion which could
explain the constitutive expression
of MLS
B resistance in
strain HM1081. In the other strains, duplication
of a TAAA motif within
the sequence for the leader peptide generated
a stop codon which could
lead to the synthesis of a shorter peptide.
However, this truncation of
the leader peptide did not result
in constitutive expression. The
amplification products fused with
the
lacZ gene on the
shuttle vector pJIM2246 were introduced into
S. aureus
RN4220, and the
-galactosidase activity in S20 extracts
from cells
noninduced or induced with erythromycin or ketolides
was measured
(Table
3). In the absence of induction,
all fused
genes directed the synthesis of various basal levels of
-galactosidase.
Consistent with the constitutive expression of
MLS
B resistance
in
S. agalactiae HM1081,
the basal level of
-galactosidase synthesis
in
S. aureus
RN4220 containing the corresponding
ermAM-lacZ
fusion
was high and showed only a small increase after culture in the
presence of erythromycin (Table
3). By contrast, the low level
of
production of
-galactosidase directed by fusions from inducibly
resistant strains HM3, HM28, and HM34 increased after culture
in the
presence of erythromycin or RU 62252 by 5.4 to 9.7 times.
For
S. pneumoniae HM30, a higher basal level of
-galactosidase
was
measured; however, production of the enzyme increased slightly
(by 1.7 times) after growth in the presence of an inducer. For
strains
inducibly resistant to MLS
B antibiotics, HMR 3004 was
a
very weak inducer which increased
-galactosidase synthesis
by 1.3 to
1.9 times (1.2 times for HM30) only. In all experiments,
the activity
of chloramphenicol acetyltransferase (expressed as
micromoles per
minute per milligram of protein) encoded by plasmid
pJIM2246 was
monitored in S20 extracts from induced or noninduced
cells and remained
stable.
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FIG. 1.
Sequence alignment of attenuators of
ermAM-related genes. pAM77, S. sanguis
(17); Ef HM3, E. faecalis HM3; Pn HM28, Pn HM30,
and Pn HM34, S. pneumoniae HM28, HM30, and HM34,
respectively; Sa HM1081, S. agalactiae HM1081. Only
differences from the sequence of ermAM are shown. Deletions
are indicated by dashes. Putative promoters ( 35, 10),
ribosome-binding sites (SD1 and SD2), and sequences for the control
peptide and methylase are underlined. Stop codons are underlined and
are in italics.
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TABLE 3.
-Galactosidase activity in S20 extracts from
induced and noninduced S. aureus RN4220 cells
containing ermAM-lacZ fusions
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| |
DISCUSSION |
The mechanism of inducible expression of resistance to
MLSB antibiotics in streptococci and enterococci has been
assigned to the structures of sequences upstream from the
ermAM genes on the basis of their similarity to the
regulatory region of the ermC gene from staphylococcal
plasmid pE194 (17, 33). Deletion of most of the regulatory
region led to constitutive expression of resistance in S. agalactiae HM1081 and of -galactosidase production in the
corresponding gene fusion.
The ketolide HMR 3004 was active against most erythromycin-resistant
streptococci (Table 1) (2, 3, 10). This property could be
related either to the affinity of the drug for methylated ribosomes or
to a lack of inducing capacity. It has been shown that certain
11,12-carbonate analogs of erythromycin and 11,12-carbamate analogs of
clarithromycin retained, at least in part, affinity for methylated
ribosomes (12, 14). However, the differences in the MICs of
HMR 3004 for strains with inducible and constitutive MLSB
resistance suggested that the in vitro efficacy of the antibiotic against most erythromycin-resistant streptococci was related to the
fact that the drug has a weak or no inducing ability (3). Consistent with that proposal, the MICs of HMR 3004 significantly increased after induction of the cells with erythromycin. Fusion experiments confirmed that HMR 3004 was a very weak inducer of -galactosidase synthesis. The observation that its cladinose counterpart, RU 66252, was a potent inducer indicated that replacement of a cladinose sugar by a keto function plays a key role in the change
of the inducing capability of the ketolide. This moiety has been shown
to be responsible, at least in part, for the induction of
MLSB resistance in staphylococci (4). The
relationship between the structure of the ketolides and the loss of the
capacity to induce the ribosomal methylase remains to be thoroughly
studied.
HMR 3004 was moderately active against S. pneumoniae HM30
and E. faecalis HM3, although these strains displayed
inducible resistance to erythromycin (Table 2). Analysis of the 3' ends of the putative attenuators from five inducible strains showed that a
stem-loop structure which might sequester the initiation sequences for
the methylase in the absence of inducer could form (Fig.
2). However, point mutations in the
attenuator of strain HM30 resulted in a stem-loop structure which was
potentially less stable than those of the other inducible strains. This
could have resulted in an elevated basal level of -galactosidase
production and, presumably, an elevated basal level of the methylase in
strain HM30 and thus to relative resistance to HMR 3004. Alternatively, several substitutions in the promoter region were observed (Fig. 1),
and these could account for the increased basal level of expression of
ermAM. It has been shown that an increase in the basal
levels of the ermC methylase due to mutations in the
regulatory region or to an increase in the copy number of the plasmid
allowed the host to grow on media containing a noninducing macrolide
(34). By contrast, analysis of the regulatory region of
ermAM from E. faecalis HM3 did not
provide any clue as to the reduced activity of HMR 3004 against this
strain with inducible resistance to MLSB antibiotics.
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FIG. 2.
Potential secondary structures of the 3' ends of
attenuators from the strains with inducible MLSB
resistance. (A) S. sanguis (pAM77); (B) E. faecalis HM3; (C) S. pneumoniae HM28 and HM34; (D)
S. pneumoniae HM30. The free energy ( G) contribution is
expressed in kilocalories. The ribosome-binding sites for methylase are
underlined; the first nucleotides for methylase are boxed.
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Of note, the MICs of HMR 3004 against constitutively resistant
streptococci were increased (Table 1) but remained, by far, lower than
those of the other macrolides. The higher intrinsic activity of this
compound against susceptible streptococci may explain the lower MICs
for resistant organisms (2).
| |
ACKNOWLEDGMENTS |
This work was supported by a grant from Hoechst-Marion-Roussel.
We thank Pierre Renault for the gift of plasmid pJIM2246 and Patrice
Courvalin for reading the manuscript.
| |
FOOTNOTES |
*
Corresponding author. Present mailing address: CHU de
Caen, Service de Microbiologie, Avenue Côte de Nacre, 14033 Caen
cedex, France. Phone: (33) 2 31 06 45 72. Fax: (33) 2 31 06 45 73. E-mail: leclercq-r{at}chu-caen.fr.
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Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
