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In vitro and in vivo activities of novel, semisynthetic thiopeptide inhibitors of bacterial elongation factor Tu

Whitehead, Lewis and Deng, Gejing and Lee, Lac and Chenail, Gregg and Leeds, Jennifer and Luu, Catherine and Palestrant, Deborah and Sachdeva, Meena and Yu, Robert and Lamarche, Matthew (2011) In vitro and in vivo activities of novel, semisynthetic thiopeptide inhibitors of bacterial elongation factor Tu. Antimicrobial Agents and Chemotherapy, 55 (11). pp. 5277-5283. ISSN 0066-4804

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 (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. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections 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. faecalis infections with ED50 of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

Item Type: Article
Date Deposited: 10 Mar 2018 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/20520

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