Sixty strains of Pseudomonas aeruginosa were selected from our clinical stock cultures and used as donors of drug resistance to examine the presence of R factors. They were highly resistant to one or more of six drugs including tetracycline (TC), chloramphenicol (CM), streptomycin (SM), sulfanilamide (SA), carbenicillin (CPC), and kanamycin (KM). Three FP − , auxotrophic mutants of P. aeruginosa were used as recipients, which had been made resistant to either rifampin (RMP) or KM by in vitro mutation. Each donor was mated with each of the three recipients, and 45 strains were found to transfer their resistance to one or more recipients. A second series of conjugation experiments using 45 exconjugants as donors showed that 23 could transfer their resistance. We conclude that these strains carry R factors that are transmissible to one or more recipients. Eleven carried resistance to (TC.CM.SM.SA.CPC), nine to (TC.CM.SM.SA), one to (TC.CM.SA.CPC), one to (TC.CM.SA), and one to (SM). All of these R factors could not be transmitted to other species belonging to the family Enterobacteriaceae .

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Changes in nitric oxide (NO) concentration and cerebral blood flow (CBF) in the parietal cortex during hypercapnoea were investigated in anaesthetized rats, using a NO-selective electrode and laser Doppler flowmetry. When hypercapnoea was induced by inhalation of 5% CO2 for 10 min, both the NO concentration and CBF increased. After administration of 7-nitroindazole, a neuronal NO synthase (nNOS) inhibitor, both the basal NO and CBF decreased, and responses to hypercapnoea were also significantly suppressed by 70.1% and 73.2%, respectively, compared with the control state. These results suggest that NO derived from nNOS is involved not only in maintaining resting cerebral circulation but also in regulating CBF response during hypercapnoea.

In the course of our screening program for new antibacterial compounds, a strain A24566 isolated from a lichen collected at Jyogasaki, Shizuoka prefecture, Japan, was found to produce a potent antibiotic. This compound, BE-24566B (1), was isolated from the mycelial cake of cultural broth, and was shown to have the unique structure in Fig. 1 Characterization of the strain followed the method adopted by the International Streptomyces Project (ISP)1}. The strain A24566 formed well developed and branching substrate mycelia and aerial mycelia, but fragmentation of the substrate mycelia was not observed. The whole cell hydrolysate contained L,L-diaminopimelic acid. The spore chains of the strain were spirals and the spore surface was rugose. The spore mass was gray, becoming black and moist with maturity.Melanoid pigments and soluble pigments were absent. Utilization of carbon sources was examined according to the method of Pridham and Gottlieb2) on the agar medium culture at 28°C for 14 days. D-glucose, D-xylose, L-arabinose, L-rhamnose, D-fructose, raffinose, sucrose and D-galactose were utilized for growth. Utilization of inositol was doutful and salicin was not utilized by the The strain A24566, cultured on a slant agar medium, was inoculated into four 500-ml volume Erlenmeyer flasks which contained 110ml of a culture medium comprising 0.2% glucose, 2.0% dextrin, 0.5% meat meal, 0.5% degreased rice bran, 0.2% degreased meat bone powder, 0.1% dry yeast, 0.05% magnesium sulfate, 0.05% sodium bromide, 0.5% sodium chloride, 0.1% potassium hydrogen phosphate, 0.002% calcium chlo- hours. Twoml each of the culture broth was inoculated into 100 of 500-ml volume Erlenmeyer flasks containing 110ml of the foregoing culture medium and placed on a rotary shaker (180rpm) at 28°C for 120hours. The broth (ca. 1 1 liters) so obtained was filtered to give mycelium. Methanol (8 liters) was added to the resulting mycelium and stirred at room temperature for 30 minutes, then the mycelium was filtered yielding the methanol extract. The methanol extract was concentrated to about 1 liter under reduced pressure and then 1.5 liters of ethyl acetate was added for extraction. Fresh ethyl acetate (0.7liter) was added to the resulting aqueous layer to perform second extraction and the ethyl acetate extracts were combined. The extract was washed twice with water (1 literx2) and then concentrated under reduced pressure. To the resulting residue 240ml of methanol and 400ml of n-hexane were added and the methanol layer was separated. To the n-hexane layer 50ml of methanol was added and methanol layer was separated. The two methanol layers were combinedand evaporated under reduced pressure. The resulting residue was dissolved with 200ml of chloroform and applied to a column of silica gel (3x38cm) and the column was developed with solvent mixture (chloroform -meth-

The in vivo activity of BO-3482, which has a dithiocarbamate chain at the C-2 position of 1beta-methyl-carbapenem, was compared with those of vancomycin and imipenem in murine models of septicemia and thigh infection with methicillin-resistant Staphylococcus aureus (MRSA). Because BO-3482 was more susceptible than imipenem to renal dehydropeptidase I in a kinetic study of hydrolysis by this renal enzyme, the therapeutic efficacy of BO-3482 was determined during coadministration with cilastatin. In the septicemia models, which involved two homogeneous MRSA strains and one heterogeneous MRSA strain, the 50% effective doses were, respectively, 4.80, 6.06, and 0.46 mg/kg of body weight for BO-3482; 5.56, 2.15, and 1.79 mg/kg for vancomycin; and >200, >200, and 15.9 mg/kg for imipenem. BO-3482 was also as effective as vancomycin in an MRSA septicemia model with mice with cyclophosphamide-induced immunosuppression. In the thigh infection model with a homogeneous MRSA strain, the bacterial counts in tissues treated with BO-3482-cilastatin were significantly reduced in a dose-dependent manner compared with the counts in those treated with vancomycin and imipenem-cilastatin (P < 0.001). These results indicate that BO-3482-cilastatin is as effective as vancomycin in murine systemic infections and is more bactericidal than vancomycin in local-tissue infections. The potent in vivo activity of BO-3482-cilastatin against such MRSA infections can be ascribed to the good in vitro anti-MRSA activity and improved pharmacokinetics in mice when BO-3482 is combined with cilastatin and to the bactericidal nature of the carbapenem.