Kenji Namba

In Vitro and In Vivo Antibacterial Activities of DC-159a, a New Fluoroquinolone

ABSTRACT DC-159a is a new 8-methoxy fluoroquinolone that possesses a broad spectrum of antibacterial activity, with extended activity against gram-positive pathogens, especially streptococci and staphylococci from patients with community-acquired infections. DC-159a showed activity against Streptococcus spp. (MIC90, 0.12 μg/ml) and inhibited the growth of 90% of levofloxacin-intermediate and -resistant strains at 1 μg/ml. The MIC90s of DC-159a against Staphylococcus spp. were 0.5 μg/ml or less. Against quinolone- and methicillin-resistant Staphylococcus aureus strains, however, the MIC90 of DC-159a was 8 μg/ml. DC-159a was the most active against Enterococcus spp. (MIC90, 4 to 8 μg/ml) and was more active than the marketed fluoroquinolones, such as levofloxacin, ciprofloxacin, and moxifloxacin. The MIC90s of DC-159a against Haemophilus influenzae, Moraxella catarrhalis, and Klebsiella pneumoniae were 0.015, 0.06, and 0.25 μg/ml, respectively. The activity of DC-159a against Mycoplasma pneumoniae was eightfold more potent than that of levofloxacin. The MICs of DC-159a against Chlamydophila pneumoniae were comparable to those of moxifloxacin, and DC-159a was more potent than levofloxacin. The MIC90s of DC-159a against Peptostreptococcus spp., Clostridium difficile, and Bacteroides fragilis were 0.5, 4, and 2 μg/ml, respectively; and among the quinolones tested it showed the highest level of activity against anaerobic organisms. DC-159a demonstrated rapid bactericidal activity against quinolone-resistant Streptococcus pneumoniae strains both in vitro and in vivo. In vitro, DC-159a showed faster killing than moxifloxacin and garenoxacin. The bactericidal activity of DC-159a in a murine muscle infection model was revealed to be superior to that of moxifloxacin. These activities carried over to the in vivo efficacy in the murine pneumonia model, in which treatment with DC-159a led to bactericidal activity superior to those of the other agents tested.

Effect of β-1,6-Glucan Inhibitors on the Invasion Process of Candida albicans: Potential Mechanism of Their In Vivo Efficacy

ABSTRACT β-1,6-Glucan is a fungus-specific cell wall component that is essential for the retention of many cell wall proteins. We recently reported the discovery of a small molecule inhibitor of β-1,6-glucan biosynthesis in yeasts. In the course of our study of its derivatives, we found a unique feature in their antifungal profile. D21-6076, one of these compounds, exhibited potent in vitro and in vivo antifungal activities against Candida glabrata. Interestingly, although it only weakly reduced the growth of Candida albicans in conventional media, it significantly prolonged the survival of mice infected by the pathogen. Biochemical evaluation of D21-6076 indicated that it inhibited β-1,6-glucan synthesis of C. albicans, leading the cell wall proteins, which play a critical role in its virulence, to be released from the cell. Correspondingly, adhesion of C. albicans cells to mammalian cells and their hyphal elongation were strongly reduced by the drug treatment. The results of the experiment using an in vitro model of vaginal candidiasis showed that D21-6076 strongly inhibited the invasion process of C. albicans without a significant reduction in its growth in the medium. These evidences suggested that D21-6076 probably exhibited in vivo efficacy against C. albicans by inhibiting its invasion process.

Antimycobacterial Activities of Novel Levofloxacin Analogues

ABSTRACT In order to investigate structure-activity relationships between antimycobacterial activities and basic substituents at the C-10 position of levofloxacin (LVFX), we synthesized a series of pyridobenzoxazine derivatives by replacement of theN-methylpiperazinyl group of LVFX with various basic substituents. A compound with a 3-aminopyrrolidinyl group had one-half the activity of LVFX against Mycobacterium avium, M. intracellulare, and M. tuberculosis. Mono- and dimethylation of the 3-amino moiety of the pyrrolidinyl group increased the activities against M. avium and M. intracellulare but not those against M. tuberculosis. On the other hand, dialkylation at the C-4 position of the 3-aminopyrrolidinyl group enhanced the activities against M. avium, M. intracellulare, and M. tuberculosis. Thus, introduction of an N-alkyl or aC-alkyl group(s) into the 3-aminopyrrolidinyl group may contribute to an increase in potency against M. avium,M. intracellulare, and/or M. tuberculosis, probably through elevation of the lipophilicity. However, among the compounds synthesized, compound VII, which was a 2,8-diazabicyclo[4.3.0]nonanyl derivative with relatively low lipophilicity, showed the most potent activity against mycobacterial species: the activity was 4- to 32-fold more potent than that of LVFX and two to four times as potent as that of gatifloxacin. These results suggested that an increase in the lipophilicity of LVFX analogues in part contributed to enhancement of antimycobacterial activities but that lipophilicity of the compound was not a critical factor affecting the potency.