In vitro and in vivo activities of novel, semi-synthetic thiopeptide inhibitors of bacterial Elongation Factor Tu

Aminothiazole derivatives of GE2270 A are novel, semi-synthetic analogs of the thiopeptide class of natural products. These derivatives, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of development candidates LDI028 and LDK733. These cycloalklycarboxylic acid derivatives possess activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. Here we describe in vitro and in vivo activities of LDI028 and LDK733 compared to marketed antibiotics. LDI028 and LDK733 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and 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 tuf gene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. LDI028 and LDK733 were investigated in a mouse systemic infection model and protected mice from lethal S. aureus infections with 50% effective doses (ED50) of 5.2 and 4.3 mg/kg, respectively. Similarly, LDI028 and LDK733 protected mice from lethal systemic E. faecalis infections with ED50 0.56 and 0.23 mg/kg, respectively. In summary, LDI028 and LDK733 are promising development candidates for difficult to treat Gram-positive bacterial infections. Moreover, the aminothiazole carboxylic acid analogs of the natural product GE2270 A described herein represent a promising new class of antibacterials for use in human therapy