T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent and selective inhibitory activity against influenza virus. In an in vitro plaque reduction assay, T-705 showed potent inhibitory activity against influenza A, B, and C viruses, with 50% inhibitory concentrations (IC 50 s) of 0.013 to 0.48 g/ml, while it showed no cytotoxicity at concentrations up to 1,000 g/ml in Madin-Darby canine kidney cells. The selectivity index for influenza virus was more than 2,000. It was also active against a neuraminidase inhibitorresistant virus and some amantadine-resistant viruses. T-705 showed weak activity against non-influenza virus RNA viruses, with the IC 50 s being higher for non-influenza virus RNA viruses than for influenza virus, and it had no activity against DNA viruses. Orally administered T-705 at 100 mg/kg of body weight/day (four times a day) for 5 days significantly reduced the mean pulmonary virus yields and the rate of mortality in mice infected with influenza virus A/PR/8/34 (3 ؋ 10 2 PFU). These results suggest that T-705 may be a compound that is useful and highly selective against influenza virus infections and that has a mode of action different from those of commercially available drugs, such as amantadine, rimantadine, and neuraminidase inhibitors.

T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has a potent and selective inhibitory activity against influenza virus. We studied the effects of an infectious dose on the anti-influenza virus activities of T-705 and oseltamivir, a commercially available neuraminidase inhibitor, both in vitro and in vivo. Plaque formation of influenza A/PR/8/34 virus was completely inhibited by 10 µg/ml of T-705 after 72 h incubation, whereas visible plaque formation was detected in the plate treated with GS 4071, the active form of oseltamivir (10 µg/ml). The antiviral activity of T-

The corticospinal (CS) tract is essential for voluntary movement, but what we know about the organization and development of the CS tract remains limited. To determine the total cortical area innervating the seventh cervical spinal cord segment (C7), which controls forelimb movement, we injected a retrograde tracer (fluorescent microspheres) into C7 such that it would spread widely within the unilateral gray matter (to Ͼ80%), but not to the CS tract. Subsequent detection of the tracer showed that, in both juvenile and adult mice, neurons distributed over an unexpectedly broad portion of the rostral two-thirds of the cerebral cortex converge to C7. This even included cortical areas controlling the hindlimbs (the fourth lumbar segment, L4). With aging, cell densities greatly declined, mainly due to axon branch elimination. Whole-cell recordings from spinal cord cells upon selective optogenetic stimulation of CS axons, and labeling of axons (DsRed) and presynaptic structures (synaptophysin) through cotransfection using exo utero electroporation, showed that overgrowing CS axons make synaptic connections with spinal cells in juveniles. This suggests that neuronal circuits involved in the CS tract to C7 are largely reorganized during development. By contrast, the cortical areas innervating L4 are limited to the conventional hindlimb area, and the cell distribution and density do not change during development. These findings call for an update of the traditional notion of somatotopic CS projection and imply that there are substantial developmental differences in the cortical control of forelimb and hindlimb movements, at least in rodents.

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Our results suggest that decreased bactericidal activity, or the in vitro PAE of carbapenems and fluoroquinolones, is related to the reduced in vivo protective effect against infection caused by high inoculum with S. aureus or P. aeruginosa.

Valosin-containing protein mutations are not rare in Asian patients, and gene analysis should be considered for patients with adult-onset rimmed vacuolar myopathy with neurogenic changes. A wide variety of central and peripheral nervous system symptoms coupled with rare bone abnormalities may complicate diagnosis.

Cyclothialidine is a new DNA gyrase inhibitor isolated from Streptomycesfilipinensis NR0484. Structurally, it belongs to a new class of natural products containing a unique 12-membered lactone ring that is partly integrated into a pentapeptide chain When ATP is present, DNA gyrase catalyzes the introduction of negative supercoils into DNA; in the absence of ATP, it removes negative supercoils, albeit inefficiently. The mammalian topoisomerase, however, can only relax supercoiled DNA. DNA gyrase has proved to be essential for bacterial growth. These factors provide the basis for DNA gyrase inhibitors to exert their antibacterial activities with selective toxicities. DNA gyrase is known to be the target of two classes of antibiotics. One comprises the synthetic quinolones, typified by nalidixic acid and oxolinic acid, which target the A subunit of the enzyme and probably act by interfering with the DNA rejoining step of the gyrasemediated DNA strand-passing reaction (14,27,30). The other class consists of the natural coumarin-type compounds, such as novobiocin and coumermycin Al, that inhibit gyrase probably by competing with ATP for binding to the B subunit of the enzyme (7,8,15,29). Although synthetic quinolones are commercially successful antibacterial agents, there is still room for improvement in their toxicities (33) and activities against resistant strains (6, 26). The natural novobiocin derivatives are also toxic. These situations led us to initiate microbial broth screening for DNA gyrase inhibitors with the aim of identifying new lead compounds. From the screening of natural products for DNA gyrase inhibitors, we discovered a novel DNA gyrase inhibitor, cyclothialidine (Ro 09-1437) (Fig. 1) (1). It was isolated from the fermentation products of Streptomyces * Corresponding author. filipinensis NR0484. Cyclothialidine contains a unique 12-member lactone ring which is partly integrated into a pentapeptide chain. In this report, we describe the biological activity of cyclothialidine as a lead structure for a new class of antibacterial agents. MATERIALS AND METHODSChemicals. Cyclothialidine (molecular weight, 641; >98% pure) was isolated from the culture broth of S. filipinensis NR0484. Nalidixic acid, oxolinic acid, novobiocin, coumermycin Al, and adriamycin were purchased from Sigma Chemical Company. Ofloxacin (Daiichi), norfloxacin (Kyorin), ciprofloxacin (Bayer), and enoxacin (Dainippon) were >98% pure by high-pressure liquid chromatographic analysis. All other chemicals were at least analytical grade. DNA

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