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Antimicrobial Agents and Chemotherapy, July 2005, p. 2729-2734, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2729-2734.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antibacterial Properties of Some Cyclic Organobismuth(III) Compounds

Toshiaki Kotani,¹ Daisuke Nagai,¹ Kensuke Asahi,¹ Hitomi Suzuki,² Fumiaki Yamao,³ Nobumasa Kataoka,⁴ and Tatsuo Yagura^1*

Departments of Bioscience,¹ Chemistry, Faculty of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda-shi, Hyogo-ken 669-1337,² National Institute of Genetics, 111 Yata, Mishima, Shizuoka-ken 411-0801,³ Department of Medical Technology, Kobe University of School of Medicine, Kobe 654-0142, Japan⁴

Received 2 July 2004/ Returned for modification 8 September 2004/ Accepted 28 March 2005

Top Abstract Introduction Materials and Methods Results Discussion References

 
Bismuth compounds are known for their low levels of toxicity in mammals, and various types of bismuth salts have been used to treat medical disorders. As part of our program to probe this aspect of bismuth chemistry, cyclic organobismuth compounds 1 to 8 bearing a nitrogen or sulfur atom as an additional ring member have been synthesized, and their antimicrobial activities against five standard strains of gram-negative and gram-positive bacteria were assessed. The eight-membered-ring compounds, compounds 1 to 3, exhibited MICs of less than 0.5 µg/ml against Staphylococcus aureus and were more active than the six-membered ones, compounds 5 to 8 (MICs, 4.0 to 16 µg/ml). The gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Enterococcus faecalis) were more susceptible to both types of ring compounds than the gram-negative ones (Escherichia coli and Pseudomonas aeruginosa). Treatment with polymyxin B nonapeptide increased the susceptibility of E. coli to cyclic organobismuth compounds, indicating the low permeability of the outer membrane of gram-negative bacteria to the compounds. Compound 1 also had activity against methicillin-resistant S. aureus, which had an MIC for 90% of the hospital stock strains of 1.25 µg/ml. The killing curves for S. aureus treated with compound 1 or 3 revealed a static effect at a low dose (2x the MIC). However, when S. aureus was treated with 10x the MIC of compound 1 or 3, there was an approximately 3-log reduction in the viable cell number after 48 h of treatment. Electron microscopic inspection demonstrated a considerable increase in the size of S. aureus and the proportion of cells undergoing cell division after treatment with compound 1 at 0.5x the MIC.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Bismuth is a unique element in terms of its low level of toxicity and noncarcinogenic nature, despite its heavy metal status. Traditionally, inorganic bismuth compounds have found widespread uses in medicine and veterinary practice. Various types of bismuth salts have been introduced as fungicides. They are also used as medicines for the treatment of gastrointestinal disorders due to their astringent, bacteristatic, and disinfectant actions (1, 2, 13). However, bismuth salts exhibit only modest antibacterial activity (3).

Since the 1990s, the physiological aspect of bismuth chemistry has received considerable attention, and much effort has been devoted to the synthesis of different types of bismuth compounds in order to improve their antibacterial activities (2, 4-6, 10). Pharmacological investigation of new bismuth compounds has led to the development of medications with interesting activities for the treatment of infectious diseases. As part of our program to develop bismuth-based organic compounds with enhanced antibacterial activities, we have synthesized several new cyclic organobismuth compounds and assessed their activities against standard strains of gram-negative and gram-positive bacteria in order to address the structure-function relationships of bismuth compounds.

In this report we demonstrate the activities of these novel compounds against typical gram-negative and gram-positive bacteria and elucidate the mechanism by which these compounds exert their antimicrobial effects.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Cyclic organobismuth compounds. Bi-chlorophenothiabismin-S,S-dioxide (compound 5), bi-(4-methylphenyl)phenothiabismin (compound 8), and the S,S-dioxide of compound 8 (compound 6) were reported previously (12). Other cyclic bismuth compounds tested for their antibacterial activities (compounds 1 to 4 and 7) were synthesized by the routes shown in Fig. 1. A common methodology was used to construct the bismacycle structures; an appropriate substrate was doubly lithiated with butyllithium at low temperature, and the resulting dianion was treated with anhydrous bismuth chloride. For brevity, therefore, we only describe herein the typical procedures for the synthesis of compounds 3 and 4. The details of the synthesis and properties of the other compounds will be published in a journal that specializes in organic compound synthesis.

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FIG. 1. Routes of synthesis of compounds 1 and 2 (A), compounds 3 and 4 (B), and compounds 5 to 7 (C). BuLi, butyllithium.

Bi-chlorodibenzo[c,f][1,5]thiabismocine (compound 3). To a well-stirred suspension of bis(2-lithiobenzyl) sulfide generated from bis(2-bromobenzyl) sulfide (3.72 g, 10 mmol) and tert-butyllithium (22 mmol) in ether (100 ml) was added dropwise a solution of BiCl₃ (6.31 g, 20 mmol) in the same solvent (40 ml) at –78°C. The resulting mixture was stirred for 12 h, during which time the temperature was gradually allowed to rise to room temperature. The mixture was poured into cold brine (100 ml), ethyl acetate (150 ml) was added, and insoluble material was removed by filtration. The organic layer was separated and dried over anhydrous MgSO₄. The solvent was removed under reduced pressure to leave a yellow oil, which was chromatographed on alumina by using hexane-ethyl acetate (3:1) as the eluent and which was recrystallized from the same solvent to afford compound 3 as colorless crystals (1.78 g, 39%). Melting point, 180 to 183°C; _H 4.25 (2H, d, J_AB 15.3, 5- and 7-H), 4.51 (2H, d, J_AB 15.3, 5- and 7-H), 7.36 (2H, dt, J 1.3 and 7.2, ArH), 7.48 to 7.56 (4H, m, ArH), and 8.80 (2H, d, J 7.2, ArH); _C 41.05, 127.98, 130.83(2C), 139.11, 147.63, and 173.66; _max(KBr)/cm^–1 3,050, 2,961, 1,433, 1,408, 754, 737, 721, and 434; m/z 421 (44%, M-Cl), 367 (2, M-C₆H₄CH₂-1), 365 (6, M-C₆H₄CH₂-1), 331 (7, BiC₆H₄CH₂), 241 (5, BiS), 212 (49, M-BiCl), 209 (100, Bi), and 122 (3, C₆H₄CH₂S). Found: C, 36.41%; H, 2.53%. C₁₄H₁₂BiClS requires C, 36.81%; H, 2.65%.

Bi-(4-methylphenyl)dibenzo[c,f][1,5]thiabismocine (compound 4). To a stirred solution of compound 3 (457 mg, 1 mmol) in tertrahydrofuran (10 ml) was added a solution of 4-methylphenylmagnesium bromide (ca. 1.5 mmol) in the same solvent (1.5 ml) at room temperature. After 1 h, the mixture was quenched by the addition of brine (5 ml) and extracted with ethyl acetate (20 ml, three times). The organic extract was dried over MgSO₄ and concentrated under reduced pressure to leave an oil, which was chromatographed on alumina by using hexane as the eluent and which was recrystallized from hexane to afford compound 4 as colorless crystals (451 mg, 88%). Melting point, 116 to 118°C; _H 2.32 (3H, s, Me), 3.65 (2H, d, J_AB 13.8, 5- and 7-H), 3.72 (2H, d, J_AB 13.8, 5- and 7-H), 7.19 to 7.24 (4H, m, ArH), 7.30 (2H, dt, J 1.4 and 7.5, ArH), 7.49 (2H, dd, J 1.4 and 7.5, ArH), 7.70 (2H, dd, J 1.4 and 7.5, ArH), and 7.71 (2H, d, J 7.5, ArH); _C 21.45, 36.46, 128.46, 128.90, 131.32(2C), 137.19, 137.46, 137.96, 145.66, 154.19 and 157.46; _max(KBr)/cm^–1 3,048, 2,919, 1,433, 795, 754, 737, 723, and 480; m/z 512 (M⁺, 1%), 422 (12, M-C₆H₄CH₂), 421 (69, M-C₆H₄Me), 331 (3, BiC₆H₄CH₂S), 300 (20, BiC₆H₄Me), 241 (5, BiS), 212 (9, M-BiC₆H₄Me), 209 (100, Bi), and 122 (2, C₆H₄CH₂S). Found: C, 48.74%; H, 3.83%. C₂₁H₁₉BiS requires C, 49.22%; H, 3.74%.

The cyclic organobismuth compounds obtained were dissolved in sterile dimethyl sulfoxide (DMSO) (analytical grade; Sigma, St. Louis, Mo.) and were stored frozen at –40°C until they were used. As these compounds were almost insoluble in water, we prepared aqueous solutions of the desired concentration by adding a DMSO solution of the bismuth compound into water drop by drop with vigorous stirring.

Bacterial strains. Bacterial reference cultures were used to test a broad spectrum of bacteria. The strains used in this study were Escherichia coli NBRC15034, Staphylococcus aureus NBRC 14462, Bacillus subtilis NBRC 16449, Pseudomonas aeruginosa NBRC 13275, and Enterococcus faecalis NBRC12965. Clinical isolates of methicillin-resistant S. aureus (MRSA) were obtained from among the clinical isolates stocked at the Medical School of Kobe University.

Identification of S. aureus was performed by the coagulase test with human plasma. MRSA strains were confirmed to be methicillin resistant by testing for methicillin susceptibility and by PCR detection of the mecA gene.

Susceptibility experiments. MICs were determined by an agar dilution or broth microdilution method, in accordance with the procedures outlined by CLSI (formerly the NCCLS) (11). For the agar dilution method, inocula were adjusted to yield approximately 5 x 10⁴ CFU/spot. Mueller-Hinton broth agar (MHA) (Difco) was used to determine the MICs. Precultures were grown to mid-log phase at 37°C for 4 h in Muller-Hinton broth (MHB) medium for B. subtilis and E. coli and in brain heart infusion broth (BHI) medium (Difco) for S. aureus and E. faecalis. P. aeruginosa was precultured in MHB medium containing 0.4% KNO₃. Bismacycles were added in duplicate agar plates (final DMSO concentration, less than 5%), and the cultures were incubated for 24 h at 37°C. The MIC endpoint was defined as the lowest drug concentration that inhibited all visible growth. Negative controls treated with solvent (DMSO) and positive controls containing a range of streptomycin or ampicillin concentrations were added to each set of experiments. DMSO at a final concentration of 5% (vol/vol) had no effect on cell growth or viability.

MRSA strains were tested for susceptibility in MHB medium. The bacteria were tested with compound 1 over a wide range of concentrations (0.025 to 2.5 µg/ml). The MIC was expressed as the concentration of compound 1 that inhibited visual growth for 20 ± 2 h.

Time-kill analysis. Time-kill analyses were performed in MHB medium with 2% NaCl by a previously described method (8). The S. aureus cells were grown to the logarithmic phase by preincubation of the inoculum (5 x 10⁵ CFU/ml) in fresh medium prior to the addition of drug. Aliquots were removed at 0, 2, 8, 24, and 48 h after drug addition; and after they were washed with MHB medium, 50 µl of the undiluted aliquot and 10-fold serial dilutions of the aliquot were plated onto MHA plates for viable count determination. The plates were incubated at 35°C for 48 h, and the numbers of colonies that formed were counted.

Electron microscopy. All cultures were grown to an optical density at 625 nm of 0.1 in BHI medium prior to processing for electron microscopic examination. The S. aureus cells were cultured at 37°C in 10 ml of BHI medium in two series of tubes containing either no drug or 0.125 µg/ml of compound 1. The cells were harvested when they were in the exponential growth phase (18 h), fixed in 0.1% glutaraldehyde and 3% paraformaldehyde in 0.1 M phosphate buffer (pH 7.2) for 2 h, and then rinsed twice in 0.2 M cacodylate buffer (pH 7.2). They were treated with 1% osmium tetroxide in cacodylate buffer for 1 h at 4°C. Cells were embedded in 2% agar in cacodylate buffer, treated with 0.5% uranyl acetate, and then dehydrated with graded concentrations of ethanol. After the agar blocks containing cells were rinsed with propiren oxide, they were embedded in Epon. Ultrathin sections were stained with lead acetate and then examined with a transmission electron microscope (JEOL100S) and photographed. Cell size was calculated from the photographs with the use of the Scion Image tool.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Synthesis and chemical structures of organobismuth(III) compounds. We have synthesized eight cyclic organobismuth compounds, compounds 1 to 8 (Fig. 2). These cyclic compounds were chosen due to their high degrees of stability brought about by fusion with benzene rings.

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FIG. 2. Structures of the synthetic cyclic organobismuth(III) compounds used in this study: compound 1, N-tert-butyl-bi-chlorodibenzo[c,f][1,5]azabismocine; compound 2, N-tert-butyl-bi-(4-methylphenyl)dibenzo[c,f][1,5]azabismocine; compound 3, bi-chlorodibenzo[c,f][1,5]thiabismocine; compound 4, bi-(4-methylphenyl)dibenzo[c,f][1,5]thiabismocine; compound 5, bi-chlorophenothiabismin-S,S-dioxide; compound 6, bi-(4-methylphenyl)phenothiabismin-S,S-dioxide; compound 7, bi-vinylphenothiabismin-S,S-dioxide; and compound 8, bi-(4-methylphenyl)phenothiabismin.

The eight-membered cyclic organobismuth(III) compounds, compounds 1 and 2, were synthesized according to the route depicted in Fig. 1A. Dibenzyl(tert-butyl)amine was doubly lithiated with tert-butyllithium and treated with anhydrous bismuth chloride to give 1-tert-butyl-12-chlorodibenzo[c,f][1,5]azabismocine (compound 1), which, on further treatment with a Grignard reagent, gave biarylated dibenzo[c,f][1,5]azabismocine (compound 2). Biarylated dibenzo[c,f][1,5]thiabismocine (compound 3) was obtained from bis(2-bromobenzyl) sulfide via halogen-metal exchange, followed by treatment with bismuth chloride, as shown in Fig. 1B. Subsequent arylation of compound 3 with the Grignard reagent gave the biarylated product (compound 4). Six-membered cyclic organobismuth(III) compounds, bisubstituted phenothiabismin-1,1-dioxides (compounds 5 to 7), were synthesized starting from diphenyl sulfone via double lithiation with butyllithium, followed by treatment with bismuth chloride, along the pathway illustrated in Fig. 1C. Biarylated dibenzo[c,f][1,5]thiabismocine 8 was obtained in a manner similar to that for bis(2-bromobenzyl) sulfide. Cyclic bismuth compounds 1 to 8 were stable crystalline solids with high melting points. Although ordinary organobismuth(III) compounds bearing the BiCl bond are moisture sensitive and readily decompose under atmospheric conditions, compounds 1, 3, and 5 were comparatively stable and could be stored for months in the dark without appreciable degradation. The enhanced chemical stability of these cyclic compounds may be attributed to the transannular coordinative interaction between the nitrogen, sulfur, or oxygen atom and the bismuth center, which would make the bismuth less susceptible to attack by water molecules.

Antimicrobial activities of organobismuth(III) compounds. In order to examine the potential activities of the organobismuth(III) compounds as new antibacterial agents, their activities against standard strains of gram-negative and gram-positive bacteria were tested in vitro. The MICs determined for five strains are given in Table 1, which also contains the results for reference antibiotics, determined under the same experimental conditions for comparison. As can be seen, all the bismacycles demonstrated antimicrobial activity against the three standard gram-positive bacterial strains, although the six-membered-ring compounds displayed weaker activities than the eight-membered ring compounds, compounds 1 to 3. Eight-membered-ring compounds 1 to 3 were less active against the gram-negative bacteria than the gram-positive bacteria, while the six-membered-ring compounds and eight-membered ring compound 4 exhibited no toxicity toward the gram-negative bacteria at the concentrations tested. The same MICs were obtained by broth microdilution (data not shown). Thus, the bismocine structure is generally more efficient than the bismine structure.

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TABLE 1. Antimicrobial activities of eight bismuth compounds against five species of bacteria assayed by the agar dilution method

Effect of PMBNP on susceptibility of E. coli to bismacycles. The six-membered-ring compounds and compound 4 exhibited no growth inhibition of the gram-negative bacteria at the concentrations tested, while they exerted apparent antibiotic activity against gram-positive bacteria. In order to understand this selectivity, the MICs of bismacycles against E. coli were studied in the presence of polymyxin B nonapeptide (PMBNP), a compound well known for its ability to affect gram-negative bacteria (14, 15). As shown in Table 1, it was found that PMBNP made E. coli susceptible to the six-membered-ring compounds and compound 4, although the MICs were still four- to eightfold higher than those against gram-positive bacteria. These results suggest that the absence of an antibacterial effect of those compounds on gram-negative bacteria results from the low permeability of the outer membranes of gram-negative bacteria to these bismacycles. Nevertheless, the differences in the susceptibilities of the permeabilized gram-negative bacteria to each bismacycle were similar to those of the gram-positive bacteria, indicating that the chemical structures are important for their antibacterial properties.

Activity of compound 1 against methicillin-resistant Staphylococcus aureus. The compound 1 MIC for S. aureus was 0.25 µg/ml (Table 1). Next, we tested the activity of compound 1 against several clinical isolates of MRSA. The compound 1 MIC for MRSA (ATCC 43300) was fivefold higher than the MIC for S. aureus (NBRC14462), and the MIC at which 90% of strains are inhibited for clinical isolates of MRSA was 1.25 µg/ml (Table 2).

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TABLE 2. Testing of susceptibilities of MRSA strains to compound 1 assayed by the broth microdilution method

Time-kill experiment. Compounds 1 and 3 showed antibacterial effects. Then, we studied the antibacterial properties of compound 1. Figure 3 shows the time course of the growth-inhibiting activity of compound 1 against S. aureus. Although compound 1 demonstrated antibacterial activity, no reduction in the optical density at 600 nm of the culture even at 4x the MIC was observed. Next, to determine whether compound 1 has bacteriostatic or bactericidal activity, the time-killing kinetics of compound 1 were investigated. As can be seen in Fig. 4A, compound 1 at 2x to 5x the MIC inhibited growth, but there was only a small reduction in the number of bacteria that formed colonies on the agar plate after 48 h exposure. We obtained the same result after 72 h exposure to 2x the MIC (data not shown). However, if the concentration of compound 1 increased to 10x the MIC, the number of viable bacteria decreased after 48 h exposure. We obtained similar results using compound 3 (Fig. 4B). Thus, these results indicate that compounds 1 and 3 are bacteriostatic rather than bactericidal at low doses, while they are bactericidal when S. aureus is exposed to high concentrations of these compounds.

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FIG. 3. Effect of compound 1 on the growth of S. aureus. Cells were grown in MHB medium, and compound 1 was added to the culture at the following concentrations (at time zero): control (no drug added; ), 0.125 µg/ml (0.5x the MIC; ), 0.5 µg/ml (2x the MIC; x); 1.0 µg/ml (4x the MIC; ). The growth rate gradually decreased with an increase in the drug concentration.

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FIG. 4. Killing curves for compounds 1 (A) and 3 (B) tested against S. aureus. Compound 1 or 3 was added to the logarithmic phase of S. aureus broth cultures at 30°C. At the indicated times, 10 ml of culture was withdrawn, placed on ice, and subsequently washed by three cycles of centrifugation with MHB medium. After the final wash, the bacteria were resuspended in MHB medium and viable counts were made in triplicate on MHB agar plates. Control (no drug addition; ); 2x the MIC (); 5x the MIC (); 10x the MIC (x).

Transmission electron microscopy. To gain insight into the bioactivities of the bismacycles, thin-sectioned S. aureus from a broth culture exposed to a subinhibitory concentration of compound 1 was examined. S. aureus exposed to compound 1 was swollen relative to the control cultures, and the proportion of cells in which the cytoplasm appeared to be separated by the new cell wall increased significantly (Fig. 5). These cells seem to be undergoing cell division, suggesting that a part of the antibacterial activity of compound 1 may be attributable to retardation of the completion of cell division.

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FIG. 5. Transmission electron microscopy. (A) Thin section of untreated S. aureus culture for 18 h. Staining was with uranyl acetate-lead citrate. (B) Thin section of S. aureus culture after exposure to compound 1 at 0.125 µg/ml for 18 h. The morphology of the treated bacteria is very similar to that of the bacteria in the control culture, except that many cells are larger and the proportion of dividing cells (ca. 40%) is significantly higher than that in the control culture (ca. 5%). Bar, 1 µm.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Bismuth salts have been extensively used as antimicrobial agents, and as cataloged by Briand and Burford (2), many bismuth-containing compounds with apparent chemical complexity exhibit therapeutic or antibacterial activity. Thus, bismuth compounds should be promising pharmaceutical agents. One of the purposes of this study was to prepare new bismuth complexes potentially applicable to bismuth-based chemotherapy. We have succeeded in synthesizing a series of heterocyclic bismuth(III) compounds with different chemical complexities (12). Among these new compounds, eight-membered-ring compounds 1 and 3 have apparent bactericidal activities against S. aureus. The weak activities of the six-membered-ring compounds and compound 4 against the gram-negative bacteria were improved by the simultaneous addition of PMBNP to the culture, indicating that the weak activity results from the low permeability of the outer membrane to the bismacycles.

We note that the bismuth compounds used in this study may be classified into three groups according to their antibacterial activities. Prominent activity was observed with compounds 1 to 3, while moderate activity was exhibited by compounds 4, 6, and 7. Compounds 5 and 8 were weak in their actions. All eight-membered-ring compounds except compound 4 exhibited stronger antimicrobial activities than the six-membered-compounds, compounds 5 to 8. Compounds 1 and 3 were particularly active, where the bismuth and chlorine atoms can undergo transannular interaction with the nitrogen or sulfur atom via a hypervalent transition state. The study of the variable temperature dynamic ¹H nuclear magnetic resonance spectra of compound 3 demonstrated a reversible inversion of the stereochemistry at the bismuth center, which takes place via the edge inversion process, as illustrated in Fig. 6. Compound 5 also has a BiCl bond, but such an interaction is infeasible for the rigid six-membered-ring structure. Compound 2 lacks the BiCl bond, but the phenyl group on the bismuth can act as a substitute for the chlorine on electronic grounds. In accord with this, the antimicrobial activity observed for compound 2 was comparable to that observed for compounds 1 and 3. Since ordinary noncyclic organobismuth compounds are relatively inactive against bacteria (7, 9; our unpublished results), we may attribute the enhanced antimicrobial activities of cyclic organobismuth compounds 1 to 3 to some electronic state of the bismuth atom that arises during the ring inversion process. However, at present, the reason why compound 4 exhibited low levels of activity is unknown.

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FIG. 6. Reversible inversion of stereochemistry at the bismuth center of compound 3 demonstrated on variable temperature dynamic 1H nuclear magnetic resonance spectra. G, free energy of activation.

The eight-membered-ring bismacycles have potent antibacterial activities against gram-negative and -positive bacteria, including MRSA. Several bismuth thiol compounds have also been reported to be a group of novel biocides with potent, broad-spectrum activity against most bacteria (5) and show no cross-resistance against MRSA (6). Since the actions of the bismacycles are thought to be related to both the physical properties of bismuth and the chemical properties of heterocyclic structures, it may be more difficult for bacteria to develop resistance to these compounds. Thus, cyclic organobismuth(III) compounds, as well as bismuth thiol compounds, are suggested to be a promising group of antibacterial agents as candidates for development for clinical application.

 
* Corresponding author. Mailing address: Department of Bioscience, Faculty of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda-shi, Hyogo-ken 669-1337, Japan. Phone and fax: 0795-65-8473. E-mail: tyagura{at}ksc.kwansei.ac.jp.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Antimicrobial Agents and Chemotherapy, July 2005, p. 2729-2734, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2729-2734.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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