ly-146032 and Sepsis

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

Daptomycin is a novel lipopeptide antibiotic with excellent activity against Gram-positive bacterial pathogens, but its therapeutic value for the treatment of invasive pneumococcal disease compared to that for the treatment of pneumococcal pneumonia is incompletely defined. We investigated the efficacy of daptomycin in two models of Streptococcus pneumoniae-induced lung infection, i.e., pneumococcal pneumonia and septic pneumococcal disease. Mice were infected with a bioluminescent, invasive serotype 2 S. pneumoniae strain or a less virulent serotype 19 S. pneumoniae strain and were then given semitherapeutic or therapeutic daptomycin or ceftriaxone. Readouts included survival; bacterial loads; and septic disease progression, as determined by biophotonic imaging. Semitherapeutic daptomycin treatment fully protected the mice against the progression of septic disease induced by serotype 2 S. pneumoniae, while therapeutic treatment of the mice with daptomycin or ceftriaxone led to approximately 70% or approximately 60% survival, respectively. In contrast, mice infected with serotype 19 S. pneumoniae developed severe pneumonia and lung leakage even in the presence of increased intra-alveolar daptomycin levels, resulting in only 40% survival, whereas the ceftriaxone-treated mice had 100% survival. Together, although daptomycin demonstrates little efficacy in the treatment of pneumococcal pneumonia, daptomycin is highly effective in preventing S. pneumoniae-induced septic death, thus possibly offering a therapeutic option for patients with life-threatening septic pneumococcal disease.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Daptomycin; Disease Models, Animal; Mice; Mice, Inbred C57BL; Pneumococcal Infections; Pneumonia, Pneumococcal; Sepsis; Streptococcus pneumoniae

The in vitro activity of TR-700 (torezolid) was evaluated against a collection of 660 staphylococcal blood isolates. TR-700 showed excellent activity against all the staphylococci tested. The MIC(50) and MIC(90) values of TR-700, linezolid, daptomycin, and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) isolates were 0.25 and 0.5, 2 and 4, 0.5 and 0.5, and 1 and 2 microg/ml, respectively. TR-700 demonstrated greater in vitro potency than linezolid against staphylococci, including linezolid-resistant and vancomycin-nonsusceptible strains, and was 32-fold more active than linezolid against the seven cfr-positive MRSA strains tested.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; In Vitro Techniques; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Sepsis; Spain; Staphylococcal Infections; Tetrazoles; Vancomycin

N-Acylated ornithine analogues of daptomycin were synthesized and tested for their antibacterial efficacy.

Topics: Animals; Anti-Bacterial Agents; Daptomycin; Mice; Microbial Sensitivity Tests; Ornithine; Sepsis; Staphylococcal Infections; Staphylococcus aureus