In vitro and in vivo antimicrobial activity of TS2037, a novel aminoglycoside antibiotic
| Autor: | Shoichi Murakami, Yoshihisa Akiyama, Hideki Fushimi, Yoko Hirai, Yukiko Hiraiwa, Kazunori Maebashi, Daishiro Ikeda, Takayuki Usui, Nobuto Minowa |
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| Rok vydání: | 2018 |
| Předmět: |
Methicillin-Resistant Staphylococcus aureus
0301 basic medicine medicine.drug_class 030106 microbiology Antibiotics medicine.disease_cause Cell Line Microbiology Mice 03 medical and health sciences chemistry.chemical_compound Drug Resistance Bacterial Drug Discovery medicine Animals Pseudomonas Infections Arbekacin Pharmacology Kanamycin Kinase business.industry Aminoglycoside Dibekacin Epithelial Cells Staphylococcal Infections biochemical phenomena metabolism and nutrition bacterial infections and mycoses Anti-Bacterial Agents Aminoglycosides chemistry Staphylococcus aureus Amikacin Pseudomonas aeruginosa Linezolid Vancomycin Kidney Diseases Gentamicin business medicine.drug |
| Zdroj: | The Journal of Antibiotics. 71:363-371 |
| ISSN: | 1881-1469 0021-8820 |
| Popis: | 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-β-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. |
| Databáze: | OpenAIRE |
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