linezolid and Respiratory-Tract-Infections

Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Drug Discovery; Gram-Negative Bacteria; Half-Life; Hydrogen Bonding; Isoquinolines; Microbial Sensitivity Tests; Potassium Channels; Rats; Respiratory Tract Infections; Solubility; Urea

Utilizing a fully synthetic route to tetracycline analogues, the C-9 side-chain of the fluorocyclines was optimized for both antibacterial activity and oral efficacy. Compounds were identified that overcome both efflux (tet(K), tet(A)) and ribosomal protection (tet(M)) tetracycline-resistance mechanisms and are active against Gram-positive and Gram-negative organisms. A murine systemic infection model was used as an oral efficacy screen to rapidly identify compounds with oral bioavailability. Two compounds were identified that exhibit both oral bioavailability in rat and clinically relevant bacterial susceptibility profiles against major respiratory pathogens. One compound demonstrated oral efficacy in rodent lung infection models that was comparable to marketed antibacterial agents.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Biological Availability; Cyclophosphamide; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Lung; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Neutropenia; Rats; Rats, Sprague-Dawley; Respiratory Tract Infections; Ribosomes; Sepsis; Stereoisomerism; Structure-Activity Relationship; Tetracycline Resistance; Tetracyclines

The genes erm(B), mef(A), and both erm(B) and mef(A) were identified in 42.6, 10.1, and 47.3%, respectively, of the erythromycin-resistant Streptococcus pneumoniae isolates. Of the strains, 3.8% were nonsusceptible to levofloxacin and had 1 to 6 amino acid changes in the quinolone resistance-determining region, including a new mutation, Asn94Ser, in the product of parC. Levofloxacin with reserpine was highly specific for efflux screening.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; DNA, Bacterial; Drug Resistance, Bacterial; Erythromycin; Fluoroquinolones; Genes, Bacterial; Hospitals; Humans; Korea; Levofloxacin; Macrolides; Microbial Sensitivity Tests; Molecular Epidemiology; Mutation; Ofloxacin; Pneumococcal Infections; Polymerase Chain Reaction; Prevalence; Reserpine; Respiratory Tract Infections; Retrospective Studies; Streptococcus pneumoniae