| Autor: |
Leeds, J. A., LaMarche, M. J., Brewer, J. T., Bushell, S. M., Deng, G., Dewhurst, J. M., Dzink-Fox, J., Gangl, E., Jain, A., Lee, L., Lilly, M., Manni, K., Mullin, S., Neckermann, G., Osborne, C., Palestrant, D., Patane, M. A., Raimondi, A., Ranjitkar, S., Rann, E. M., Sachdeva, M., Shao, J., Tiamfook, S., Whitehead, L., Yu, D. |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; August 2011, Vol. 55 Issue: 11 p5277-5283, 7p |
| Abstrakt: |
ABSTRACTRecently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitroand in vivoactivities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureusand vancomycin-resistant enterococci (MIC90≤ 0.25 μg/ml) but weaker against the streptococci (MIC90≥ 4 μg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tufgene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureusinfections with 50% effective doses (ED50) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalisinfections with ED50of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitroand in vivoactivity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy. |
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