novobiocin and Respiratory-Tract-Infections

Topics: Acute Disease; Anti-Bacterial Agents; Bacitracin; Bronchitis; Chloramphenicol; Chronic Disease; Ear Diseases; Humans; Labyrinth Diseases; Laryngitis; Neomycin; Novobiocin; Otitis Externa; Otitis Media; Penicillins; Pneumococcal Infections; Polymyxins; Respiratory Tract Infections; Staphylococcal Infections; Streptococcal Infections; Streptomycin; Tetracycline; Tonsillitis; Tracheal Diseases

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

Topics: Animals; Dog Diseases; Dogs; Drug Combinations; Drug Therapy, Combination; Novobiocin; Respiratory Tract Infections; Tetracyclines

Topics: Cephaloridine; Chloramphenicol; Drug Combinations; Erythromycin; Fusidic Acid; Germany, West; Humans; Lincomycin; Microbial Sensitivity Tests; Nitrofurans; Novobiocin; Penicillin Resistance; Penicillins; Respiratory Tract Infections; Serotyping; Sputum; Streptococcus pneumoniae; Sulfamethoxazole; Sulfonamides; Tetracycline; Trimethoprim; Vancomycin

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Cephaloridine; Chloramphenicol; Colistin; Erythromycin; Escherichia coli; Female; Gentamicins; Humans; Kanamycin; Lincomycin; Male; Meningitis; Microbial Sensitivity Tests; Middle Aged; Novobiocin; Penicillins; Radiography; Respiratory Tract Infections; Sepsis; Staphylococcus; Streptococcus; Streptomycin; Sulfonamides; Tetracycline; Urinary Tract Infections

Topics: Child; Dermatology; Focal Infection; Focal Infection, Dental; Humans; Infant; Novobiocin; Otitis; Pediatrics; Pharyngitis; Respiratory Tract Infections; Sinusitis; Tetracycline

Topics: Anti-Bacterial Agents; Chlortetracycline; Dermatology; Drug Resistance; Drug Resistance, Microbial; Erythromycin; Gastroenterology; In Vitro Techniques; Kitasamycin; Leukemia; Methicillin; Novobiocin; Osteomyelitis; Otolaryngology; Penicillins; Pharmacology; Research; Respiratory Tract Infections; Rifamycins; Staphylococcus; Streptococcus; Urinary Tract Infections

Topics: Asthma; Bronchiectasis; Bronchitis; Humans; Novobiocin; Pneumonia; Respiratory Tract Infections; Tetracycline

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Humans; Infections; Lung Diseases; Novobiocin; Respiratory Tract Infections; Urinary Tract Infections

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Humans; Infections; Lung Diseases; Novobiocin; Respiratory Tract Infections; Urinary Tract Infections

Topics: Humans; Hypersensitivity; Novobiocin; Respiratory Tract Infections

Topics: Biological Phenomena; Novobiocin; Physiological Phenomena; Respiratory System; Respiratory Tract Infections

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Dermatologic Agents; Humans; Novobiocin; Phosphates; Protein Synthesis Inhibitors; Respiratory System; Respiratory Tract Infections; Tetracycline