In Vitroand In VivoActivities of Novel, Semisynthetic Thiopeptide Inhibitors of Bacterial Elongation Factor Tu

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.