AT-4140, 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, showed broad and potent antibacterial activity. Its MICs for 90% of the strains tested were 0.1 to 0.78 ,ug/mi against gram-positive organisms, such as members of the genera Staphylococcus, Streptococcus, and Enterococcus, and 0.0125 to 1.56 ,ug/ml against gram-negative organisms, such as members of the family Enterobacteriaceae and the genera Pseudomonas, Branhamella, Campylobacter, Haemophilus, and Neisseria. Its MICs were 0.025 to 0.78 ,ig/ml against glucose nonfermenters, such as members of the genera Xanthomonas, Acinetobacter, Alcaligenes, Moraxella, Flavobacterium, and Brucella; 0.2 to 0.78 ,ug/mi against anaerobes, such as Clostridium perfringens and Bacteroides fragilis; 0.0125 to 0.05 p.g/ml against Legionella spp.; 0.0125 to 0.2 ,ug/ml against Mycoplasma spp.; 0.031 to 0.063 ,u.g/ml against Chlamydia spp.; and 0.1 to 0.3 ,ig/ml against Mycobacterium spp. The potencies of AT-4140 against gram-negative organisms were comparable to those of ciprofloxacin and higher than those of ofloxacin, enoxacin, and norfloxacin. The potencies of AT-4140 against gram-positive organisms, glucose nonfermenters, anaerobes, Mycoplasma spp., Chlamydia spp., and Mycobacterium spp. were generally higher than those of the quinolones with which AT-4140 was compared. AT-4140 showed good oral efficacy against systemic infections with Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, and Pseudomonas aeruginosa in mice. Its efficacy was better when a daily dose was given once than when it was given in two doses. Good efficacies of the orally administered drug were also observed in pulmonary, dermal, and urinary tract infection models in mice. The in vivo efficacies of AT-4140 were equal to or better than those of ciprofloxacin, ofloxacin, enoxacin, and norfloxacin.New quinolones used clinically these days have a broad spectrum of activity against both gram-positive and gramnegative organisms. However, some important pathogens, such as streptococci, enterococci, Mycoplasma spp., Chlamydia spp., and Mycobacterium spp., are not sufficiently susceptible to the quinolones. To improve this point, we screened of this group of compounds and found a new compound called AT-4140 (Fig. 1) with a broader antibacterial spectrum. This paper describes the in vitro and in vivo antibacterial activities of AT-4140 compared with those of ciprofloxacin, ofloxacin, enoxacin, and norfloxacin.(
The pharmacokinetics of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (AT-4140) in experimental animals given a single oral dose of 5 mg/kg were studied. The mean peak levels of AT-4140 in plasma of mice, rats, dogs, and monkeys were 0.25, 0.50, 1.14, and 0.49 ,ug/ml, respectively, with mean elimination half-lives of 5.0, 3.8, 8.0, and 11.7 h, respectively. The oral bioavailability of AT-4140 calculated from the ratio of the areas under the concentration-time curve after oral and intravenous administration was 77% in dogs. The levels of AT-4140 in tissue in mice and rats were 1 to 11 times higher than the levels in plasma and 4 to 9 times higher than those of ciprofloxacin in mice. The mean 24-h biliary recovery of AT-4140 in rats was 5.6% of the dose and became 21.3% after (3-glucuronidase treatment. The mean 48-h urinary recoveries of AT-4140 in mice, rats, dogs, and monkeys were 6.7, 12.9,-8.6, and 12.7%, respectively, of the dose and were 7.8, 16.3, 8.9, and 18 Nakamura, Chem. Abstr. 107:236733v, 1987) and ciprofloxacin (4) were synthesized in our laboratory as reported previously. Doses and concentrations of the drugs are expressed in terms of the free bases.Animals. The animals used were male Std-ddY mice weighing 22 to 38 g, male Wistar rats weighing 190 to 270 g, male beagle dogs weighing 11 to 13 kg, and male cynomolgus monkeys weighing 3.7 to 5.4 kg.Drug administration. For oral administration, AT-4140 was suspended in 0.2% carboxymethylcellulose sodium solution (for mice and rats) or 0.5% gum tragacanth solution (for monkeys) and ciprofloxacin was dissolved in deionized water to avoid its aggregation in 0.2% carboxymethylcellulose sodium solution (for mice). Both the drugs were packed in gelatin capsules for oral administration to dogs. For intravenous administration, the drugs were dissolved in physiological saline with an appropriate amount of NaOH if necessary. The drugs were administered once at a dose of 5 mg/kg to animals that had fasted overnight, unless otherwise specified.Preparation of assay samples. Blood was withdrawn by cardiac puncture from mice and rats under ether anesthesia at 0.25, 0.5, 1, 2, 4, 6, and 8 h postadministration and by * Corresponding author.venipuncture from dogs and monkeys at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration and 0.1, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after intravenous administration. Blood samples were centrifuged to separate the plasma. Organs and tissues were harvested from exsanguinated mice 0.5, 1, 2, 4, 6, and 8 h postadministration and from exsanguinated rats 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h postadministration. Spinal fluid was taken from the same rats by puncturing the atlanto-occipital membrane by the method of Yaksh and Rudy (17) before exsanguination. Tissue extracts were prepared as described previously (9). Bile was collected from rats through a polyethylene catheter introduced into the common bile duct by surgery and pooled for 0 to 3, 3 to 6, and 6 to 24...
Spontaneous mutants with various patterns of resistance to pipemidic acid (PPA), piromidic acid (PA), and nalidixic acid (NAL) were isolated from Escherichia coli K-12. Most mutants were less resistant to PPA than to PA and NAL, and some mutants resistant to PA and NAL were hypersusceptible to PPA. As for the mutants tested, resistance to the drugs was conferred by mutations at nalA and new nal genes designated as nalC and nalD, both of which were located at about 82 min on the recalibrated map. Resistance to PA and NAL was due to decreased sensitivity of the bacterial DNA synthesizing system to them and insufficient drug transport, whereas resistance to PPA was only due to the former.Pipemidic acid (PPA) (11) is a synthetic antibacterial agent mainly active against gramnegative bacteria, including Pseudomonas aeruginosa (15). It is structurally related to piromidic acid (PA) (14) and nalidixic acid (NAL) (10) as shown in Fig. 1. Cross-resistance among the drugs is so incomplete that bacteria highly resistant to PA and NAL are inhibited by PPA at relatively low concentrations (15). To study this incomplete cross-resistance, spontaneous mutants with various patterns of resistance to the drugs were isolated from Escherichia coli K-12. Most mutants were less resistant to PPA than to PA and NAL, and some mutants resistant to PA and NAL were, on the contrary, more susceptible to PPA than the parent strain. Genetic analysis of several mutants showed that resistance to these drugs was conferred by nalA (7) and new nal genes, designated as n#lC and D, mapped at about 82 min oia the recalibrated linkage map of E. coli K-12, (1). These genes determined sensitivity; oft4e-Icterial DNA synthesizing system to the dhrs with or without potentiation of ethylenediaminetetraacetate (EDTA) effect.Incomplete cross-resistance among PPA, PA, and NAL would be accounted for by differences in resistance genes, drug sensitivity of the bacterial DNA synthesizing system, and drug transport. MATERIALS AND MErHODSBacteria and phage. All of the bacteria used are derivatives of E. coli K-12. The strains KL-16 (Hfr, thi reUA), JC1552 (F-, leu trp his argG metB lacYgal malA xyl mtl strA tonA tsx supE), and AB3505 (F-, proA trp his ilvD metE argH lacY or Z galK xyl mtl malA tsx) were obtained from B. J. Bachmann. The strain 5199, a thyA derivative of JC1552, was made by trimethoprim selection. Spontaneous mutants resistant to PPA, PA, and NAL (N-21, N-24, N-31, N-51, P-5, and P-18) were isolated from E. coli KL-16 by plating it on nutrient agar containing PPA or NAL at graded concentrations. Plkc was supplied by H. Ogawa.Drugs. PPA, PA, and NAL were produced as described previously (11, 14) in our laboratories. Equimolar NaOH was added for the dissolution of these compounds in water. Streptomycin sulfate was a product of Dainippon Pharmaceutical Co., Ltd. [6-3H]thymidine (25 Ci/mmol) was purchased from The Radiochemical Centre.Media. Nutrient agar was purchased from Eiken Co., Ltd. F-top agar, R-top agar, and LB medium or agar (12), L broth (9), ...
The pharmacokinetis of AT-2266 (1-ethyl-luoro-1,4-dihydro-4oxo-7-(1-piperazinyl)
In Escherichia coli K-12 mutants which had a new nalidixic acid resistance mutation at about 82 min on the chromosome map, cell growth was resistant to or hypersusceptible to nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, and novobiocin. Deoxyribonucleic acid gyrase activity as tested by supercoiling of A phage deoxyribonucleic acid inside the mutants was similarly resistant or hypersusceptible to the compounds. The drug concentrations required for gyrase inhibition were much higher than those for cell growth inhibition but similar to those for inhibition of A phage multiplication. Transduction analysis with A phages carrying the chromosomal fragment of the tnaA-gyrB region suggested that one of the mutations, nal-31, was located on the gyrB gene.Nalidixic acid (NA) (27), oxolinic acid (OA) (24), piromidic acid (PA) (34), and pipemidic acid (PPA) (29) are synthetic antibacterial compounds having a pyridonecarboxylic acid moiety as a common chemical structure and are mainly active against gram-negative bacteria (9,43,45,46). These compounds specifically inhibit bacterial DNA synthesis with little effect on RNA and protein synthesis around their miniimal inhibitory concentrations (6,43). The inhibition of DNA synthesis is so rapid that the compounds are considered to act during the elongation of DNA chains (6, 10).Recently, two research groups found that NA and OA inhibited an enzyme called DNA gyrase (15,50). This enzyme introduces negative superhelical turns into duplex DNA (16) and is considered to play an important role in metabolic processes involving DNA (7,25,38). Gyrase from Escherichia coli consists of two subunits, A and B (20). Subunit A is a homodimer of a 105,000dalton protein encoded by the gyrA (formerly nalA) gene, which determines resistance to NA, and subunit B consists of a 95,000-dalton protein encoded by the gyrB (formerly cou) gene, which determines resistance to novobiocin (NB) and coumermycin Al (20,35). Subunit A from an NA-resistant gyrA mutant and subunit B from a coumermycin Ar-resistant gyrB mutant each reconstitute a gyrase with the expected drug resistance. The gyrA gene is located at approximately 48 min, and the gyrB gene is at approximately 82 min on the genetic map of Escherichia coli K-12 (2). Cross-resistance is usually observed among pyridonecarboxylic acid derivatives, but it is so incomplete that bacteria which are highly re-sistant to NA are inhibited by some of them, e.g., PPA, at relatively low concentrations (46). During a study on the mode of incomplete crossresistance, two new types of NA resistance mutations were found at about 82 min, i.e., nal-21 and nal-31 (formerly naiC), and nal-24 (formerly nalD) (22). The nal-21 or nal-31 mutation caused resistance to NA and PA but also hypersusceptibility to PPA. The nal-24 mutation, like NA resistance gyrA mutations, conferred resistance to all three drugs. The nal-21, nal-31, and nal-24 mutations were no more resistant to NB by a conventional agar dilution method for the determination of miniimal inhibitory ...
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