title: 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 μg/ml) but weaker against the streptococci (MIC(90) ≥ 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 (ED(50)) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED(50) 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, CA 94608, USA. jennifer.leeds@novartis.com
authors.forename: J A
authors.initials: JA
authors.lastname: Leeds
authors.forename: M J
authors.initials: MJ
authors.lastname: LaMarche
authors.forename: J T
authors.initials: JT
authors.lastname: Brewer
authors.forename: S M
authors.initials: SM
authors.lastname: Bushell
authors.forename: G
authors.initials: G
authors.lastname: Deng
authors.forename: J M
authors.initials: JM
authors.lastname: Dewhurst
authors.forename: J
authors.initials: J
authors.lastname: Dzink-Fox
authors.forename: E
authors.initials: E
authors.lastname: Gangl
authors.forename: A
authors.initials: A
authors.lastname: Jain
authors.forename: L
authors.initials: L
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Lilly
authors.forename: K
authors.initials: K
authors.lastname: Manni
authors.forename: S
authors.initials: S
authors.lastname: Mullin
authors.forename: G
authors.initials: G
authors.lastname: Neckermann
authors.forename: C
authors.initials: C
authors.lastname: Osborne
authors.forename: D
authors.initials: D
authors.lastname: Palestrant
authors.forename: M A
authors.initials: MA
authors.lastname: Patane
authors.forename: A
authors.initials: A
authors.lastname: Raimondi
authors.forename: S
authors.initials: S
authors.lastname: Ranjitkar
authors.forename: E M
authors.initials: EM
authors.lastname: Rann
authors.forename: M
authors.initials: M
authors.lastname: Sachdeva
authors.forename: J
authors.initials: J
authors.lastname: Shao
authors.forename: S
authors.initials: S
authors.lastname: Tiamfook
authors.forename: L
authors.initials: L
authors.lastname: Whitehead
authors.forename: D
authors.initials: D
authors.lastname: Yu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010444:Peptide Elongation Factor Tu / Q000037:antagonists & inhibitors*; D010456:Peptides, Cyclic / Q000737:chemistry; D013203:Staphylococcal Infections / Q000188:drug therapy; D013844:Thiazoles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; D013844:Thiazoles; D010444:Peptide Elongation Factor Tu; C068122:GE 2270 A