In vitro and in vivo antimicrobial activity of TS2037, a novel aminoglycoside antibiotic.

To overcome serious methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infections, we synthesized TS2037, 5,4″-diepi-arbekacin, a novel aminoglycoside antibiotic, and evaluated its biological properties. TS2037 showed broad-range, as well as robust antibacterial activities against Gram-positive and Gram-negative bacteria. The MIC50 and MIC90 of TS2037 against clinical isolates of MRSA (n = 54) were both 0.25 µg/mL, and no resistant strain was observed. The MIC50 and MIC90 of TS2037 against clinical isolates of P. aeruginosa (n = 54) were 1 and 4 µg/mL, respectively. TS2037 and arbekacin, anti-MRSA aminoglycoside, were more stable against AAC(6')-APH(2″), aminoglycoside-6'-N-acetyltransferase and 2″-O-phosphotransferase, produced by resistant S. aureus than gentamicin. Therapeutic efficacies of TS2037 in the mouse models of systemic infection with MRSA were superior to those of arbekacin, vancomycin, and linezolid. The efficacy of TS2037 against systemic infection caused by P. aeruginosa producing AAC(6')-II was superior to those of arbekacin and amikacin. In the nephrotoxicity risk screening, the release of free N-acetyl-ß-D-glucosaminidase from the kidney epithelial cell line after treatment with TS2037 at 2.5 and 5.0 µM were 2.0 and 2.1 (U/L), respectively, which were about two times higher than those of arbekacin. In conclusion, TS2037 exhibited the most potent antibacterial activity among aminoglycosides tested against both MRSA and P. aeruginosa in vitro and in vivo, although its nephrotoxicity risk remains to be improved.

Liquid crystals for organic thin-film transistors.

Crystalline thin films of organic semiconductors are a good candidate for field effect transistor (FET) materials in printed electronics. However, there are currently two main problems, which are associated with inhomogeneity and poor thermal durability of these films. Here we report that liquid crystalline materials exhibiting a highly ordered liquid crystal phase of smectic E (SmE) can solve both these problems. We design a SmE liquid crystalline material, 2-decyl-7-phenyl-[1]benzothieno[3,2-b][1]benzothiophene (Ph-BTBT-10), for FETs and synthesize it. This material provides uniform and molecularly flat polycrystalline thin films reproducibly when SmE precursor thin films are crystallized, and also exhibits high durability of films up to 200 °C. In addition, the mobility of FETs is dramatically enhanced by about one order of magnitude (over 10 cm(2) V(-1) s(-1)) after thermal annealing at 120 °C in bottom-gate-bottom-contact FETs. We anticipate the use of SmE liquid crystals in solution-processed FETs may help overcome upcoming difficulties with novel technologies for printed electronics.

Self-directed orientation of molecular columns based on n-type hexaazatrinaphthylenes (HATNAs) for electron transport.

Self-organizing n-type hexaazatrinaphthylenes (HATNAs) with various bay-located side chains have been synthesized. The HATNA derivatives are able to form long-range molecular columns with self-directed growth directions. In particular, alkyl-substituted HATNAs showed in-plane molecular columns with axes parallel to substrates, whereas the columnar orientation of the HATNAs with alkylethynyl or alkylthio groups strongly depended on the length of the introduced side chains. Interestingly, the derivative with octylthio chains exhibited out-of-plane molecular columns, in which electron mobility of up to 10(-3)  cm(2) V(-1) s(-1) was determined through the time-of-flight technique, highlighting the fact that such molecular columns based on bay-substituted HATNAs are promising n-type semiconductors for device applications.

Effect of varying the 4''-position of arbekacin derivatives on antibacterial activity against MRSA and Pseudomonas aeruginosa.

4''-Deoxy-4''-episubstituted arbekacin derivatives and 4''-epi-5-deoxy-5-episubstituted arbekacin derivatives were designed and synthesized. Arbekacin and 4''-epiarbekacin both displayed the same antibacterial activity against Staphylococcus aureus (including methicillin-resistant S. aureus (MRSA)) and Pseudomonas aeruginosa. The 4''-epi-5-deoxy-5-episubstituted arbekacin derivatives showed potent antibacterial activity. Among them, the antibacterial activity of 5,4''-diepiarbekacin was superior to that of arbekacin or 5-episubstituted arbekacin against Gram-positive and Gram-negative bacteria. The 6'-N-methyl derivative of the 5,4''-diepiarbekacin was effective against P. aeruginosa expressing an aminoglycoside-modifying enzyme AAC(6')-Ib.

Synthesis and antibacterial activity of 5-deoxy-5-episubstituted arbekacin derivatives.

5-Deoxy-5-episubstituted arbekacin derivatives have been designed and efficiently synthesized. The synthetic compounds showed potent antibacterial activity against both Staphylococcus aureus, including methicillin-resistant S. aureus, and Pseudomonas aeruginosa. In particular, these derivatives were superior to arbekacin against MRSA strains expressing the bifunctional aminoglycoside-modifying enzyme AAC(6')-APH(2''). The antibacterial activity of the 5-deoxy-5-episubstituted arbekacin derivatives against Pseudomonas aeruginosa was markedly influenced by the efflux system of MexXY/OprM. The 6'-N-methyl derivative of the 5-epi arbekacin was effective against Pseudomonas aeruginosa expressing the aminoglycoside-modifying enzyme AAC(6').

Synthesis and antibacterial activity of novel neamine derivatives.

Synthesis and activity of derivatives at the O5 or O6 positions of 1-N-((S)-4-amino-2-hydroxybutyryl)-3',4'-dideoxyneamine, which is the neamine moiety of arbekacin, were reported. Among these results, the 5-O-aminoethylaminocarbonyl derivative showed effective activity against Staphylococcus aureus expressing a bifunctional aminoglycoside-modifying enzyme AAC(6')-APH(2'').

Aminoglycoside antibiotics reduce glucose reabsorption in kidney through down-regulation of SGLT1.

Nephrotoxicity is known to be a major clinical side effect of aminoglycoside antibiotics. Aminoglycosides cause damage to proximal tubular cells in kidney, however the mechanism of toxicity is still unclear. In order to elucidate the mechanism of nephrotoxicity, we studied the effect of aminoglycoside antibiotics on glucose transport systems in vitro and in vivo. As a result, we found that the aminoglycosides significantly reduced Na(+)/glucose cotransporter (SGLT1)-dependent glucose transport and also down-regulated mRNA and protein levels of the SGLT1 in pig proximal tubular LLC-PK(1) cells. To obtain evidence about SGLT1 down-regulation in vivo, we studied the mRNA expression of SGLT1 using gentamicin C-treated murine kidney and found that gentamicin C down-regulated SGLT1 in vivo as well as in vitro. Furthermore, the gentamicin C-treated mice showed significant rise in urinary glucose excretion. These results indicate that one of the mechanisms of aminoglycoside nephrotoxicity is the down-regulation of SGLT1, which causes reduction in glucose reabsorption in kidney.