ge-2270-a and Gram-Positive-Bacterial-Infections

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Carboxylic Acids; Crystallography, X-Ray; Drug Resistance, Bacterial; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Male; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Mutation; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Sepsis; Solubility; Stereoisomerism; Structure-Activity Relationship; Thiazoles

MDL 62,879 (GE2270 A) is a new peptide antibiotic that inhibits protein synthesis through an interaction with elongation factor Tu. MDL 62,879 was very active against gram-positive clinical isolates, particularly staphylococci and enterococci, for which MICs for 90% of isolates were < or = 0.13 micrograms/ml. It was equally active against isolates resistant to beta-lactams, erythromycin, gentamicin, and glycopeptides. It also had activity against Mycobacterium tuberculosis. MDL 62,879 had moderate bactericidal activity against staphylococci.

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Enterococcus; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Staphylococcus; Streptococcus; Thiazoles