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Antimicrobial Agents and Chemotherapy, June 2001, p. 1649-1653, Vol. 45, No. 6
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.6.1649-1653.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Contributions of the 8-Methoxy Group of Gatifloxacin to
Resistance Selectivity, Target Preference, and Antibacterial
Activity against Streptococcus pneumoniae
Hideyuki
Fukuda,*
Ryuta
Kishii,
Masaya
Takei, and
Masaki
Hosaka
Central Research Laboratories, Kyorin
Pharmaceutical Co., Ltd., 2399-1, Mitarai, Nogi, Shimotsuga,
Tochigi 329-0114, Japan
Received 17 November 2000/Returned for modification 15 January
2001/Accepted 19 February 2001
 |
ABSTRACT |
Gatifloxacin (8-methoxy, 7-piperazinyl-3'-methyl) at the MIC
selected mutant strains that possessed gyrA mutations at a
low frequency (3.7 × 10
9) from wild-type strain
Streptococcus pneumoniae IID553. AM-1147 (8-methoxy,
7-piperazinyl-3'-H) at the MIC or higher concentrations selected no mutant strains. On the other hand, the respective 8-H
counterparts of these two compounds, AM-1121 (8-H,
7-piperazinyl-3'-methyl) and ciprofloxacin (8-H,
7-piperazinyl-3'-H), at one and two times the MIC selected
mutant strains that possessed parC mutations at a high
frequency (>2.4 × 106). The MIC of AM-1147
increased for the gyrA mutant strains but not for the
parC mutant strains compared with that for the wild-type strain. These results suggest that fluoroquinolones that harbor 8-methoxy groups select mutant strains less frequently and prefer DNA
gyrase, as distinct from their 8-H counterparts. The in vitro activities of gatifloxacin and AM-1147 are twofold higher against the
wild-type strain, eight- and twofold higher against the first-step parC and gyrA mutant strains, respectively, and
two- to eightfold higher against the second-step gyrA and
parC double mutant strains than those of their 8-H
counterparts. These results indicate that the 8-methoxy group
contributes to enhancement of antibacterial activity against
target-altered mutant strains as well as the wild-type strain. It is
hypothesized that the 8-methoxy group of gatifloxacin increases the
level of target inhibition, especially against DNA gyrase, so that it
is nearly the same as that for topoisomerase IV inhibition in the
bacterial cell, leading to potent antibacterial activity and a low
level of resistance selectivity.
| |
INTRODUCTION |
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.
Therefore, antibiotics that possess potent activity against
penicillin-resistant as well as penicillin-susceptible S. pneumoniae are urgently needed.
Some of the recently developed fluoroquinolones have improved
activities against respiratory pathogens, including S. pneumoniae, and are expected to be useful as chemotherapeutic
agents for the treatment of patients infected with such pathogens
(1, 6, 11, 12, 20, 21, 33, 34). Recent clinical
assessments of the susceptibility of S. pneumoniae to
antibacterial agents have indicated that most clinical isolates
continue to retain their quinolone susceptibility (9, 15,
31). Nevertheless, an outbreak of quinolone-resistant S. pneumoniae has recently been reported (K. Weiss, C. Restieri, M. Laverdiere, R. J. Davidson, A. McGeer, J. De Azavedo, and D. E. Low, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother.,
Abstr. 824, p. 110, 1999). In conjunction with the increasing clinical
use of fluoroquinolone for the treatment of respiratory infections, the
increasing prevalence of quinolone resistance is anticipated in
S. pneumoniae, as recently occurred in methicillin-resistant
Staphylococcus aureus. Therefore, it is important to try to
prevent the acquisition of quinolone resistance in S. pneumoniae.
In number of studies on the in vitro selection of quinolone-resistant
strains of S. pneumoniae, investigators have reported observing different frequencies of resistance selectivity among fluoroquinolones (4, 8). It has been suggested that
gatifloxacin and clinafloxacin possess potent antipneumococcal
activities and select mutant strains less frequently than other
fluoroquinolones because of their inhibition of DNA gyrase and
topoisomerase IV (TopoIV), which occur at nearly the same levels in
bacterial cells (dual-targeting property) (8, 23). On the
other hand, it has been reported that the ease of resistance
selectivity in S. pneumoniae correlated with the
susceptibilities of the agents to the bacterial NorA-type efflux system
(4).
Gatifloxacin harbors a characteristic methoxy group at the 8 position
of the quinolone ring. The contributions of the methoxy groups of
certain fluoroquinolones, including gatifloxacin, to antibacterial
activity and/or resistance selectivity have been investigated in some
bacteria. The methoxy group has been shown to correlate with the
prevention of emergence of the mutant strains and/or potent in vitro
activity against Escherichia coli (17, 38),
S. aureus (13, 14, 39), and mycobacteria
(5, 29, 37).
In the study described in this report, we investigated the contribution
of the 8-methoxy group of gatifloxacin to resistance selectivity,
target preference, and the antibacterial activity against S. pneumoniae.
(This study was presented at the 39th Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Francisco, California, 26 to
29 September 1999.)
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MATERIALS AND METHODS |
Fluoroquinolones.
Figure 1
shows the fluoroquinolones used in the present study. Gatifloxacin
(8-methoxy, 7-piperazinyl-3'-methyl) and the structurally related
compounds ciprofloxacin (8-H,
7-piperazinyl-3'-H), AM-1121 (8-H,
7-piperazinyl-3'-methyl), and AM-1147 (8-methoxy,
7-piperazinyl-3'-H) were synthesized at Kyorin
Pharmaceutical Co., Ltd., Tokyo, Japan. These fluoroquinolones were
used for the selection of the mutant strains and susceptibility
testing.
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FIG. 1.
Chemical structures of gatifloxacin (8-methoxy,
7-piperazinyl-3'-methyl) and its structurally related compounds
ciprofloxacin (8-H, 7-piperazinyl-3'-H), AM-1121
(8-H, 7-piperazinyl-3'-methyl), and AM-1147 (8-methoxy,
7-piperazinyl-3'-H).
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|
Bacterial strains.
Quinolone-susceptible, wild-type S. pneumoniae IID553 (a type strain collected at the Institute of
Medical Science, University of Tokyo) was provided through the Japanese
Society for Bacteriology. Overnight cultures of IID553 on
Mueller-Hinton agar plates containing 5% defibrinated horse blood were
suspended in saline. The mutant strains were selected by plating the
bacterial suspension (approximately 109 CFU) on
Mueller-Hinton agar plates containing 5% defibrinated horse blood with
gatifloxacin, ciprofloxacin, AM-1121, and AM-1147 at 1, 2, 4, 8, and 16 times the MICs. The selection plates were incubated aerobically at
37°C for at least 48 h before being scored for the number of
bacterial colonies. The incidence of the appearance of resistant
strains was calculated as the ratio of the number of colonies that
emerged to the number of bacteria inoculated (in CFU).
Four types of first-step mutant strains possessing a deduced alteration
in either the GyrA subunit (S81F or S81Y) or the ParC
subunit (S79Y or
D83N) have been obtained from wild-type strain
IID553 by selection with
various fluoroquinolones (
8). The
second-step mutant
strains have continuously been selected from
the first-step
gyrA and
parC mutant strains (
9).
The results
of the second-step mutation showed that all of the
second-step
mutant strains possessed deduced alterations in both ParC
and
GyrA subunits, as described in Table
3. In order to investigate
the
antibacterial activities of gatifloxacin and its related compounds,
these first- and second-step mutant strains were used for MIC
determinations.
Mutations of QRDRs of the parC, parE, gyrA, and
gyrB genes.
To amplify gene fragments, including the
quinolone resistance-determining region (QRDRs) of the gyrA,
gyrB, parC, and parE genes, which correspond to the
QRDRs of the E. coli gyrA and gyrB genes
(35, 36), each pair of primers, the sequences of which were the same as those reported by Pan et al. (24), was
synthesized. The gene fragments were amplified, using the genomic DNAs
of S. pneumoniae strains as templates, by 25 PCR cycles on a
Perkin-Elmer thermal cycler with recombinant Taq DNA
polymerase (Takara Shuzo Co., Ltd., Shiga, Japan). The PCR conditions
were as follows: 30 s at 94°C for denaturation, 30 s at 55°C
for annealing, and 2 min at 72°C for primer extension. The
PCR-amplified gene fragments were sequenced with 5'-biotinylated
primers (5'-AAATCTGCTCGTATTACAGGGGATG-3', nucleotide
positions 187 to 211 of the gyrA gene [3];
5'-CAGGGAAACTAGCAGACTGTTCTTC-3', nucleotide positions 1238 to 1262 of the gyrB gene [25];
5'-GACAAGAGCTACCGTAAGTCGGCCAAG-3', nucleotide positions 166 to 192 of the parC gene [25];
5'-CAGCCCAATCTAAGAATCCTGCTAAG-3', nucleotide positions 1253 to 1278 of the parE gene [25]) by direct
cycle sequencing. The samples were subjected to electrophoresis in a
5% polyacrylamide gel containing 8 M urea at 45 W for 2.5 h.
Thereafter, the DNA on the gel was transferred to a nylon membrane sheet (Boehringer Mannheim GmbH, Mannheim, Germany). The dried nylon
membrane was then treated by use of a Phototope 6K detection kit (New
England Biolabs Inc., Mass.), and the bands were visualized by exposing
the membrane to X-ray film.
MIC determination.
The MICs of each fluoroquinolone for the
resistant strains were determined. The MIC was defined as the lowest
concentration of an antibacterial agent that inhibited visible growth
of the cells on Mueller-Hinton agar plates with 5% defibrinated horse blood after 18 to 20 h of incubation at 37°C (12).
| |
RESULTS AND DISCUSSION |
Resistance selection.
Gatifloxacin at the MIC selected mutant
strains at a low frequency (3.7 × 109). AM-1147 at
the MIC or higher concentrations selected no mutant strains. On the
other hand, ciprofloxacin and AM-1121 at one and two times their MICs
selected mutant strains at high frequencies (>2.4 × 106) (Table 1). These
results indicate that the compounds harboring an 8-methoxy group
selected mutant strains less frequently than their 8-H counterparts
did. For some fluoroquinolones, the presence of an 8-methoxy group has
been shown to correlate with the prevention of the emergence of mutant
strains of E. coli (38), mycobacteria (5), and S. aureus (13). The
potent bactericidal activities of the agents have been interpreted as
factors that influence resistance selectivity in these bacteria. On the
other hand, it has been reported that some fluoroquinolones selected
mutant strains of S. pneumoniae or S. aureus less
frequently, since those agents seemed to inhibit DNA gyrase and TopoIV
at nearly the same levels in bacterial cells (dual-targeting property)
(8, 23). Therefore, the dual-targeting property of the
agents that harbor an 8-methoxy group might be one of the causes of the
low frequency of resistance selectivity in S. pneumoniae.
It has been reported that the ease of resistance selectivity in
S. pneumoniae correlates with the susceptibilities of the
agents to the NorA-type efflux system (
4). We have tested
the
effects of reserpine (10 µg/ml), which is an inhibitor of the
NorA-type streptococcal PmrA efflux system (
10), on the
activities
of gatifloxacin and the related compounds. No effects of
reserpine
on the MICs of these quinolones for wild-type and mutant
strains
were observed (H. Fukuda, unpublished data). These results
suggest
that the activities of these compounds are little influenced by
the intrinsic PmrA and/or other reserpine-sensitive efflux
systems.
As described previously (
18), to investigate the
differences in the magnitude of the effects of reserpine between the
compounds
in detail, studies of the activities against
S. pneumoniae strains
that possess an activated reserpine-sensitive
efflux system will
be necessary. Unfortunately, we have no efflux
system-activated
S. pneumoniae strains. However, we have an
S. aureus norA strain
and have determined the staphylococcal
NorA efflux system susceptibilities
of some fluoroquinolones, including
gatifloxacin and ciprofloxacin,
as the ratio of the MIC for the
S. aureus norA strain to the MIC
for its parent strain (MIC
ratio) (
7). On the other hand, we
have also investigated
resistance selectivity in
S. pneumoniae (
8).
The NorA efflux system-susceptible quinolones norfloxacin
and
ciprofloxacin selected mutant strains of
S. pneumoniae at
a
high frequency. However, the NorA efflux system-resistant quinolone
sparfloxacin selected mutant strains of
S. pneumoniae at a
high
frequency. We have also investigated the antibacterial activities
of AM-1121 and AM-1147 against the
S. aureus norA strain and
its
parent strain. The NorA efflux system susceptibilities of AM-1147
and AM-1121 were almost the same as that of ciprofloxacin (MIC
ratios,
32 to 64). It is not clear, on the basis of these results,
whether the
ease of resistance selectivity in
S. pneumoniae correlates
with the susceptibilities of the agents to the NorA-type efflux
system.
Target preference.
We and other workers have already obtained
first-step mutant strains of S. pneumoniae by selection with
various fluoroquinolones (8, 11, 16, 19, 23, 24, 26, 28,
30). Trovafloxacin, levofloxacin, ciprofloxacin, and norfloxacin
select parC mutant strains, whereas gatifloxacin,
sparfloxacin, clinafloxacin, and moxifloxacin select gyrA
mutant strains. These genetic studies suggest that the former and the
latter groups of fluoroquinolones show preferences for TopoIV and DNA
gyrase, respectively. On the other hand, studies with purified
pneumococcal DNA gyrase and TopoIV have shown that TopoIV is more
sensitive to sparfloxacin and clinafloxacin according to a simple
comparison of the 50% inhibitory concentrations (IC50s)
(22, 27). The IC50s of these quinolones for
the target enzymes were determined with different in vitro assay
systems, the conditions of which were also different from the
conditions in bacterial cells. Therefore, target preference cannot
necessarily be determined by simple comparison of the IC50s in vitro. Further studies on the correlation between the
IC50 ratio (IC50 for TopoIV/IC50
for DNA gyrase) and target preference in bacterial cells will be needed.
We therefore investigated the mutations of the QRDRs in the
gyrA and
parC genes of the first-step mutant
strains selected
with gatifloxacin and its related compounds.
Gatifloxacin and
ciprofloxacin naturally selected the
gyrA
and the
parC mutant
strains, respectively (Table
2). AM-1121 selected the
parC
mutant
strains (Table
2). These results suggest that gatifloxacin
prefers
DNA gyrase and that AM-1121 and ciprofloxacin prefer TopoIV in
the wild-type strain.
No mutant strains were obtained by selection with the MIC or higher
concentrations of AM-1147 (Table
1). However, the MIC
of AM-1147
increased for the first-step
gyrA mutant strains but
not for
the first-step
parC mutant strains compared with that
for
the wild-type strain (Table
3). These
results suggest that
AM-1147 prefers DNA gyrase. In
S. aureus, we reported that the
8-methoxy groups of gatifloxacin and
AM-1147 contribute to enhancement
of DNA gyrase inhibition rather than
TopoIV inhibition (M. Takei,
H. Fukuda, Y. Oomori, and M. Hosaka,
Abstr. 40th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. 758, p. 80, 2000). Moreover,
Pestova et al. (
28) suggest that
the 8-methoxy quinolone moxifloxacin
prefer DNA gyrase in
S. pneumoniae. Therefore, the 8-methoxy groups
of the
fluoroquinolones might contribute to the target preference
for DNA
gyrase by enhancing DNA gyrase inhibition in the wild-type
S. pneumoniae strain. Some quinolones with 8-halogen groups, such
as
clinafloxacin (8-chlorine) and sparfloxacin (8-fluorine), also
prefer
DNA gyrase (
23,
26). Therefore, substituents other
than
the methoxy group at the C-8 position might be correlated
with the
target preference.
Antibacterial activity.
We previously obtained second-step
mutant strains from first-step gyrA and parC
mutant strains with gatifloxacin, trovafloxacin, levofloxacin,
ciprofloxacin, and sparfloxacin (9). All of the fluoroquinolones selected the gyrA and the parC
mutant strains from the first-step parC and gyrA
mutants, respectively. The results of studies of the second-step
mutations showed that all of the second-step mutant strains possessed
both parC and gyrA mutations (9).
To investigate the contribution of the 8-methoxy group to the
antibacterial activity, we studied the activities of gatifloxacin
and
its related compounds against various types of the target-altered
first- and second-step mutant strains as well as the wild-type
strain.
Against the wild-type strain, the activities of the 8-methoxy
quinolones gatifloxacin and AM-1147 were two-fold higher than
those of
their respective 8-H counterparts, AM-1121 and ciprofloxacin
(Table
3).
Moreover, the activities of these 8-methoxy quinolones
were eight-and
twofold higher against the first-step
parC and
gyrA mutant strains, respectively, and two- to eightfold
higher
against the second-step
gyrA and
parC
mutant strains with double
mutations (Table
3). These results indicate
that the 8-methoxy
group contributes to enhancement of antibacterial
activity against
target-altered mutant strains as well as the wild-type
strain.
The results of studies of strains with second-step mutations suggest
that the fluoroquinolones prefer DNA gyrase and TopoIV
in the
first-step
parC and
gyrA mutant strains of
S. pneumoniae,
respectively (
9). On the basis
of the assumed target preferences
of the fluoroquinolones, 8-methoxy
quinolones seem to prefer DNA
gyrase in the wild-type strains and the
parC mutant strains, and
their inhibition of DNA gyrase
might be greatly correlated with
their activities against the wild-type
and
parC mutant strains,
whereas 8-methoxy quinolones seem
to prefer TopoIV in the
gyrA mutant strains, and their
inhibition of TopoIV might be greatly
correlated with their activities
against the
gyrA mutant
strains.
The MICs of the 8-H quinolones ciprofloxacin and AM-1121 increased not
only for the first-step
parC mutant strains but also
for the
gyrA mutant strains compared with those for the wild-type
strain, although the increase in the MIC for the
gyrA mutant
strains
was less than that for the
parC mutant strains
(Table
3). This
slight crossover effect has previously been reported in
S. pneumoniae (
32) and
S. aureus
(
13). These results suggest that the preferential
target
(TopoIV) inhibition of 8-H quinolones is correlated with
the activity
against the wild-type strain and also that the secondary
target (DNA
gyrase) inhibition might be slightly involved in the
activity.
Concluding comments.
It is hypothesized that the 8-methoxy
group of gatifloxacin increases the level of target inhibition,
especially against DNA gyrase, so that it is nearly the same as that
for TopoIV inhibition in the bacterial cell, leading to potent
antibacterial activity and a low level of resistance selectivity in
S. pneumoniae, although further enzyme analysis will be
necessary to validate this hypothesis.
Alovero et al. (
2) suggested that some C-7 substituents of
fluoroquinolones affect not only antibacterial activity but
also target
preference in
S. pneumoniae. However, the piperazinyl
3'-methyl group of gatifloxacin at the C-7 position did not contribute
to enhancement of the antibacterial activities or the target
preferences
of the compounds used in the present study. Further study
of the
contribution of C-8 and C-7 substituents to target preference,
resistance selectivity, and antibacterial activity will provide
important information for the development of quinolones that possess
potent antibacterial activity and low levels of resistance
selectivity.
| |
FOOTNOTES |
*
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:
hideyuki.fukuda{at}mb2.kyorin-pharm.co.jp.
| |
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Antimicrobial Agents and Chemotherapy, June 2001, p. 1649-1653, Vol. 45, No. 6
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.6.1649-1653.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
