In Vitro and In Vivo Activities of Novel, Semisynthetic Thiopeptide Inhibitors of Bacterial Elongation Factor Tu

Abstract

Recently, 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 vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC 90 < 0.25 g/ml) but weaker against the streptococci (MIC 90 > 4 g/ml).

Codon Randomization for Rapid Exploration of Chemical Space in Thiopeptide Antibiotic Variants

“…It is worthy to note that significant semisynthetic SAR efforts by a group at Novartis have been applied to the GE2270 C -terminal tail immediately following thiazole 12. This work has provided evidence for the importance of chemical functionalities in this region of 29-membered thiopeptides for EF-Tu binding as well as increasing solubility (LaMarche, et al, 2012; Leeds, et al, 2011). …”

“…The activity, or lack thereof, for variants can be assessed by examining the reported crystal structure of GE2270 complexed with EF-Tu and the GTP analog GDPNP (Figure 6, Table S1) (Parmeggiani, et al, 2006). Important contacts between the GE2270 and EF-Tu are shown in Figure 6a and those relevant to GE37468 charted in Figure 6b (Heffron and Jurnak, 2000; LaMarche, et al, 2012; Lamarche, et al, 2012; Leeds, et al, 2011; Parmeggiani, et al, 2006). GE2270 and GE37468 have very similar antimicrobial profiles and are expected to engage in similar binding mechanisms (Stella, et al, 1995; Stella, et al, 1997).…”

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

“…Semi-synthetic derivatives have been investigated as an alternative to improve solubility of these compounds, 362–367 with GE2270 optimization eventually leading to LFF571, 368–373 a compound that has undergone clinical trials for treatment of C. difficile . 68–70 Baringolin has also been investigated through alteration of its tail.…”

Engineering von Thiopeptiden: ein multidisziplinärer Weg zu neuen Wirkstoffen

“…[56] Diese Verbindungen hatten in vitro Wirkstärken, die mit dem als Ausgangssubstanz verwendeten Naturstoff vergleichbar waren, ihre erhçhte Lçslichkeit ließ aber die In-vivo-Prüfung zu, was zu ausgezeichneten Profilen dieser Stoffe führte. [58] Die weitere Derivatisierung der Cyclohexansäure-Serie führte zur Entdeckung von LFF571 (23; Abbildung 6 b), das am Carbamatteil eine zusätzliche Alkylkette mit Carboxylgruppe trägt, was die Lçslichkeit noch weiter verbessert. [59] [60,61] und es konnte nachgewiesen werden, dass es noch immer den Elongationsfaktor Tu angreift.…”