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Antimicrobial Agents and Chemotherapy, February 1999, p. 410-412, Vol. 43, No. 2
Central Research Laboratories,
Received 6 July 1998/Returned for modification 24 August
1998/Accepted 25 November 1998
Mutants of wild-type Streptococcus pneumoniae IID553
with mutations in parC were obtained by selection with
trovafloxacin, levofloxacin, norfloxacin, and ciprofloxacin. All of the
parC mutants were cross-resistant to the selecting agents
but were not resistant to gatifloxacin and sparfloxacin. On the other
hand, gyrA mutants were isolated by selection with
gatifloxacin and sparfloxacin. The gyrA mutants were
cross-resistant to gatifloxacin and sparfloxacin but were not resistant
to the other fluoroquinolones tested. These results suggest that in
wild-type S. pneumoniae the primary target of
trovafloxacin, levofloxacin, norfloxacin, and ciprofloxacin is
topoisomerase IV, whereas the primary target of gatifloxacin and
sparfloxacin is DNA gyrase.
Streptococcus pneumoniae
is one of the most important pathogens and is responsible for
community-acquired pneumonia, acute otitis media, and meningitis.
Recently, the worldwide prevalence of penicillin-resistant S. pneumoniae has become a serious problem in clinical settings. In
such situations, the use of classes of antibiotics other than
DNA gyrase and topoisomerase IV (topo IV) serve as targets of the
fluoroquinolones in bacteria. Topo IV and DNA gyrase are thought to be
essential for DNA replication and the partition of replicated
chromosomal DNA, respectively. Fluoroquinolones inhibit these enzyme
reactions and then show antibacterial activity. DNA gyrase is known to
be a primary target of fluoroquinolones in Escherichia coli.
In contrast, topo IV seems to be a primary target of many
fluoroquinolones in some gram-positive bacteria such as
Staphylococcus aureus (4-7, 11, 18) and S. pneumoniae (8, 10, 13, 17). A recent study has
indicated that the primary target of sparfloxacin, one of the
antipneumococcal fluoroquinolones, seems to be a DNA gyrase in S. pneumoniae (14). These observations suggest that
different fluoroquinolones can have different primary targets in
S. pneumoniae. However, little information regarding the
primary targets of the fluoroquinolones exists. In the study described
here, we genetically determined the presumed primary targets of various
fluoroquinolones, including those of the antipneumococcal fluoroquinolones sparfloxacin, gatifloxacin, and trovafloxacin, and
studied the activities of these agents against target-altered mutant
strains of S. pneumoniae.
Quinolone-resistant mutants of quinolone-susceptible wild-type S. pneumoniae IID553, which was obtained from the Japanese Society
for Bacteriology, were isolated by selection. The mutants were selected
on Mueller-Hinton agar plates with 5% defibrinated horse blood. Each
plate contained 2×, 4×, 8×, 16×, and 32× the MICs of gatifloxacin,
trovafloxacin, sparfloxacin, levofloxacin, ciprofloxacin, and
norfloxacin, which were synthesized at Kyorin Pharmaceutical Co., Ltd.,
Tokyo, Japan. If no mutant was obtained by selection with these
concentrations of the agents, the mutants were selected with 1× the
MIC of the agents. The plates used for selection were incubated for at
least 48 h before the plates were scored for the number of
bacterial colonies.
The frequencies of selection of mutant strains are presented in Table
1. Resistant mutants were obtained by
selection with 16× the MIC or lower concentrations of sparfloxacin,
4× the MIC or lower concentrations of trovafloxacin, ciprofloxacin,
and norfloxacin, and 2× the MIC of levofloxacin. No mutant strain was
obtained by selection with 2× the MIC or higher concentrations of
gatifloxacin, although a mutant could be obtained by selection with 1×
the MIC of gatifloxacin.
In S. pneumoniae, the gyrA and gyrB
genes encode the GyrA and GyrB subunits of DNA gyrase, respectively,
and the parC and parE genes encode the ParC and
ParE subunits of topo IV, respectively. To amplify those gene fragments
including the quinolone resistance-determining region (QRDR) that
correspond to the QRDRs of the E. coli gyrA and
gyrB genes (19, 20), each pair of primers (sense
and antisense primers) was synthesized as described by Pan et al.
(13). The gene fragments were amplified by 25 PCR cycles
with the genomic DNA of S. pneumoniae strains as templates.
The PCR-amplified gene fragments were sequenced with 5'-biotinylated
primers (5'-AAATCTGCTCGTATTACAGGGGATG-3'; nucleotide
positions 187 to 211 of the gyrA gene [1];
5'-CAGGGAAACTAGCAGACTGTTCTTC-3', positions 1238 to 1262 of
the gyrB gene [12];
5'-GACAAGAGCTACCGTAAGTCGGCCAAG-3', positions 166 to 192 of
the parC gene [12];
5'-CAGCCCAATCTAAGAATCCTGCTAAG-3', positions 1253 to 1278 of
the parE gene [12]) by direct cycle sequencing (3).
Three mutants obtained by selection with each fluoroquinolone except
gatifloxacin were randomly chosen and then analyzed. Only one mutant
was obtained by selection with 1× the MIC of gatifloxacin, and it was
also analyzed. Two types of mutants were obtained by selection with
trovafloxacin; one of these formed smaller colonies than the parent and
the other mutants. Therefore, these two types of
trovafloxacin-resistant mutants were analyzed.
The MICs of the fluoroquinolones and the target-gene mutations for the
mutant strains are presented in Table 2.
Three types of mutants (types I to III) were obtained. Type I consisted
of mutants selected with trovafloxacin, levofloxacin, ciprofloxacin, and norfloxacin. This type of mutant possessed single-point mutations in the QRDR of the parC gene and was cross-resistant to the
selecting agents but was not resistant to gatifloxacin and
sparfloxacin. The decreases in the activities of trovafloxacin,
norfloxacin, ciprofloxacin, and levofloxacin against these
parC mutants were four-, four-, four-, and twofold,
respectively.
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Primary Targets of Fluoroquinolones in
Streptococcus pneumoniae
ABSTRACT
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-lactam antibiotics, such as fluoroquinolones, has become necessary.
Recently, antipneumococcal fluoroquinolones such as sparfloxacin,
trovafloxacin, and gatifloxacin have been developed. The
mechanisms of action of these fluoroquinolones against S. pneumoniae are under investigation (8, 10, 13, 14,
17).
TABLE 1.
Frequencies of appearance of mutant strains by selection
with various quinolones
TABLE 2.
Gene mutations in quinolone resistance-determining region
and antibacterial activities of various quinolones against the
resistant mutantsa
The second type of mutant (type II) comprised strains selected by gatifloxacin or sparfloxacin. These mutants possessed single-point mutations in the QRDR of the gyrA gene and were cross-resistant to the selecting agents but were not resistant to the other fluoroquinolones tested. The decreases in the activities of gatifloxacin and sparfloxacin against the gyrA mutants were two- and eightfold, respectively. This decrease in the activity of sparfloxacin against the gyrA mutants corresponds with those reported by Pan and Fisher (14).
The third type of mutant (type III) comprised those mutants selected with trovafloxacin. The mutants possessed no mutation in the QRDR of the target genes (gyrA, gyrB, parC, and parE). These mutants were resistant to trovafloxacin and sparfloxacin and formed colonies that were smaller than those of the parent and the other mutant strains. Some investigators have reported on quinolone-resistant mutant strains of S. pneumoniae that possess no mutation in the QRDRs of the gyrA, gyrB, parC, and/or parE genes, which suggests that these particular strains are permeability (efflux) mutants (2, 12, 13, 15, 16), one of which is cross-resistant to ethidium bromide (2). However, the type III mutants obtained in this study showed no change in susceptibility to ethidium bromide (data not shown). Further studies are necessary to analyze the mechanisms of quinolone resistance of the type III mutant strains.
Pan and Fisher (14) have reported that the mutants that possess the gyrA and parC mutations were obtained from wild-type S. pneumoniae by selection with sparfloxacin and ciprofloxacin, respectively (14). These gyrA and parC mutants were not resistant to ciprofloxacin and sparfloxacin, respectively (14). It was hypothesized from these results that the primary targets of sparfloxacin and ciprofloxacin are DNA gyrase and topo IV, respectively, in wild-type S. pneumoniae. Gootz et al. (8) have also reported that the parC mutants selected by ciprofloxacin are resistant not only to ciprofloxacin but also to trovafloxacin. These results suggest that the primary target of ciprofloxacin and trovafloxacin is likely topo IV. Regarding the target-altered resistant mutants, our results support the hypothesis and indicate that the primary targets of gatifloxacin and sparfloxacin are DNA gyrase; in addition, the primary target of trovafloxacin, levofloxacin, ciprofloxacin, and norfloxacin is topo IV in wild-type S. pneumoniae.
In S. aureus, sparfloxacin and gatifloxacin prevented the selection of quinolone-resistant grlA (parC) mutants (7, 18). The decreases in the activities of those fluoroquinolones against the grlA mutants were slight. These results suggest that agents such as sparfloxacin and gatifloxacin inhibit both DNA gyrase and topo IV at nearly the same levels (7). In this study, we showed that gatifloxacin selected mutants of S. pneumoniae at a lower frequency. Also, gatifloxacin had a slight decrease in activity (twofold) against the gyrA mutants. These observations might further suggest that gatifloxacin inhibits both wild-type DNA gyrase and topo IV at nearly the same levels in S. pneumoniae. Recently, Zhao et al. (21) have reported that fluoroquinolones with a substituted methoxy moiety at the C-8 position of the quinoline ring select quinolone-resistant mutants less frequently. Gatifloxacin also possesses a methoxy moiety at the C-8 position (9), which may explain why it prevents selection of the resistant mutants.
Since penicillin-resistant S. pneumoniae is prevalent
worldwide in clinical settings, the use of classes of antibiotics other than -lactam antibiotics, such as antipneumococcal fluoroquinolones and especially those that select for resistant mutants less frequently, will be necessary. Our observations, together with additional studies
on the target enzymes, should provide us with the necessary information
to develop potent antipneumococcal fluoroquinolones that prevent the
selection of resistant strains of S. pneumoniae.
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FOOTNOTES |
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* Corresponding author. Mailing address: Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Mitarai, Nogi, Shimotsuga, Tochigi, 329-0114 Japan. Phone: 81-280-56-2201. Fax: 81-280-57-1293. E-mail: fvbb0984{at}mb.infoweb.ne.jp.
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(2001). Fluoroquinolone Resistance Is a Poor Surrogate Marker for Type II Topoisomerase Mutations in Clinical Isolates of Streptococcus pneumoniae. J. Clin. Microbiol.
39: 2719-2721
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Fukuda, H., Kishii, R., Takei, M., Hosaka, M.
(2001). Contributions of the 8-Methoxy Group of Gatifloxacin to Resistance Selectivity, Target Preference, and Antibacterial Activity against Streptococcus pneumoniae. Antimicrob. Agents Chemother.
45: 1649-1653
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Richardson, D. C., Bast, D., McGeer, A., Low, D. E.
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45: 1911-1914
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Klepser, M. E., Ernst, E. J., Petzold, C. R., Rhomberg, P., Doern, G. V.
(2001). Comparative Bactericidal Activities of Ciprofloxacin, Clinafloxacin, Grepafloxacin, Levofloxacin, Moxifloxacin, and Trovafloxacin against Streptococcus pneumoniae in a Dynamic In Vitro Model. Antimicrob. Agents Chemother.
45: 673-678
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Boos, M., Mayer, S., Fischer, A., Köhrer, K., Scheuring, S., Heisig, P., Verhoef, J., Fluit, A. C., Schmitz, F.-J.
(2001). In Vitro Development of Resistance to Six Quinolones in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. Antimicrob. Agents Chemother.
45: 938-942
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Blondeau, J. M., Zhao, X., Hansen, G., Drlica, K.
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Khan, A. A., Slifer, T. R., Araujo, F. G., Remington, J. S.
(2001). Activity of Gatifloxacin Alone or in Combination with Pyrimethamine or Gamma Interferon against Toxoplasma gondii. Antimicrob. Agents Chemother.
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Gmuender, H., Kuratli, K., Di Padova, K., Gray, C. P., Keck, W., Evers, S.
(2001). Gene Expression Changes Triggered by Exposure of Haemophilus influenzae to Novobiocin or Ciprofloxacin: Combined Transcription and Translation Analysis. Genome Res
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Ince, D., Hooper, D. C.
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44: 3344-3350
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Bast, D. J., Low, D. E., Duncan, C. L., Kilburn, L., Mandell, L. A., Davidson, R. J., de Azavedo, J. C. S.
(2000). Fluoroquinolone Resistance in Clinical Isolates of Streptococcus pneumoniae: Contributions of Type II Topoisomerase Mutations and Efflux to Levels of Resistance. Antimicrob. Agents Chemother.
44: 3049-3054
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Heaton, V. J., Ambler, J. E., Fisher, L. M.
(2000). Potent Antipneumococcal Activity of Gemifloxacin Is Associated with Dual Targeting of Gyrase and Topoisomerase IV, an In Vivo Target Preference for Gyrase, and Enhanced Stabilization of Cleavable Complexes In Vitro. Antimicrob. Agents Chemother.
44: 3112-3117
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Poole, K.
(2000). Efflux-Mediated Resistance to Fluoroquinolones in Gram-Positive Bacteria and the Mycobacteria. Antimicrob. Agents Chemother.
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Bébéar, C. M., Grau, O., Charron, A., Renaudin, H., Gruson, D., Bébéar, C.
(2000). Cloning and Nucleotide Sequence of the DNA Gyrase (gyrA) Gene from Mycoplasma hominis and Characterization of Quinolone-Resistant Mutants Selected In Vitro with Trovafloxacin. Antimicrob. Agents Chemother.
44: 2719-2727
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Nagai, K., Davies, T. A., Pankuch, G. A., Dewasse, B. E., Jacobs, M. R., Appelbaum, P. C.
(2000). In Vitro Selection of Resistance to Clinafloxacin, Ciprofloxacin, and Trovafloxacin in Streptococcus pneumoniae. Antimicrob. Agents Chemother.
44: 2740-2746
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Fournier, B., Zhao, X., Lu, T., Drlica, K., Hooper, D. C.
(2000). Selective Targeting of Topoisomerase IV and DNA Gyrase in Staphylococcus aureus: Different Patterns of Quinolone- Induced Inhibition of DNA Synthesis. Antimicrob. Agents Chemother.
44: 2160-2165
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Marchese, A., Debbia, E. A., Schito, G. C.
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Pestova, E., Millichap, J. J., Noskin, G. A., Peterson, L. R.
(2000). Intracellular targets of moxifloxacin: a comparison with other fluoroquinolones. J Antimicrob Chemother
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Alovero, F. L., Pan, X.-S., Morris, J. E., Manzo, R. H., Fisher, L. M.
(2000). Engineering the Specificity of Antibacterial Fluoroquinolones: Benzenesulfonamide Modifications at C-7 of Ciprofloxacin Change Its Primary Target in Streptococcus pneumoniae from Topoisomerase IV to Gyrase. Antimicrob. Agents Chemother.
44: 320-325
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Brisse, S., Fluit, A. C., Wagner, U., Heisig, P., Milatovic, D., Verhoef, J., Scheuring, S., Köhrer, K., Schmitz, F.-J.
(1999). Association of Alterations in ParC and GyrA Proteins with Resistance of Clinical Isolates of Enterococcus faecium to Nine Different Fluoroquinolones. Antimicrob. Agents Chemother.
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Gootz, T. D., Zaniewski, R. P., Haskell, S. L., Kaczmarek, F. S., Maurice, A. E.
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