ge-2270-a and Staphylococcal-Infections

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.

Topics: Animals; Anti-Bacterial Agents; Cell Line; Cell Survival; Female; Hep G2 Cells; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Molecular Structure; Peptide Elongation Factor Tu; Peptides, Cyclic; Staphylococcal Infections; Thiazoles

GE37468 A is a new thiazolyl peptide antibiotic obtained by fermentation of Streptomyces sp. strain ATCC 55365. It inhibits bacterial protein synthesis by acting on elongation factor Tu and is structurally and functionally related to the GE2270 class of EF-Tu inhibitors. It is active in vitro against Gram-positive bacteria and Bacteroides fragilis, and protects mice against Staphylococcus aureus infection.

Topics: Animals; Anti-Bacterial Agents; Bacillus subtilis; Bacterial Proteins; Bacteroides fragilis; Chromatography, High Pressure Liquid; Female; Gram-Positive Bacteria; Male; Mice; Microbial Sensitivity Tests; Molecular Structure; Peptides, Cyclic; Rats; Staphylococcal Infections; Streptomyces; Thiazoles

A novel antibiotic, GE2270 A, was isolated from the fermentation broth of a strain of Planobispora rosea. The product was found to inhibit bacterial protein synthesis. Structural characteristics showed similarities between GE2270 A and thiazolyl peptides such as micrococcin which is known to inhibit protein synthesis by acting directly on the ribosome. Despite this similarity GE2270 A showed functional analogy to kirromycin-like antibiotics and pulvomycin, as its molecular target was found to be elongation factor Tu (EF-Tu). GE2270 A is active against Gram-positive microorganism and anaerobes and differs from the other EF-Tu inhibitors in its spectrum of antimicrobial activity.

Topics: Actinomycetales; Animals; Anti-Bacterial Agents; Bacteria, Anaerobic; Bacterial Proteins; Bacteroides fragilis; Gram-Positive Bacteria; Mice; Microbial Sensitivity Tests; Molecular Structure; Moraxella catarrhalis; Mycobacterium tuberculosis; Peptides; Peptides, Cyclic; Propionibacterium acnes; Protein Synthesis Inhibitors; Staphylococcal Infections; Thiazoles