Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections
| Autor: | Bernd Meibohm, Erik C. Böttger, Chetan Rathi, Richard E. Lee, Yasser M. AbdelRahman, Stefan Duscha, Zhong Zheng, Samanthi L. Waidyarachchi, David F. Bruhn, Robert J. Belland, Dora B. Madhura, Aman P. Singh, Robin B. Lee, Jiuyu Liu, Jason W. Rosch, Dimitri Shcherbakov |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Models Molecular Sexually Transmitted Diseases Bacterial Spectinomycin medicine.drug_class Antibiotics Microbial Sensitivity Tests Drug resistance Biology medicine.disease_cause Article Haemophilus influenzae Microbiology Rats Sprague-Dawley Moraxella catarrhalis Mice Structure-Activity Relationship Bacterial Proteins Drug Stability Chlorocebus aethiops Drug Discovery Drug Resistance Bacterial Streptococcus pneumoniae medicine Animals Humans Computer Simulation Drug Interactions Respiratory Tract Infections Vero Cells Bacteria Molecular Structure General Medicine biology.organism_classification medicine.disease Virology Anti-Bacterial Agents Rats Disease Models Animal Pneumococcal pneumonia Neisseria gonorrhoeae Computer-Aided Design Ribosomes medicine.drug |
| Zdroj: | Science Translational Medicine. 7 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.3010572 |
| Popis: | The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A novel series of N-benzyl substituted 3'-(R)- 3'-aminomethyl-3'-hydroxy spectinomycins was developed based on a computational analysis of the aminomethyl spectinomycin binding site and structure guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome binding 3'-(S) isomers of the leads demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target. In addition to improved antibacterial potency, compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series, compound 1, exhibited excellent chemical stability, which was superior to spectinomycin and had no significant interaction with a panel of human receptors and drug metabolism enzymes suggesting low potential for adverse reactions or drug-drug interactions in vivo. Compound 1 was active in vitro against a panel of penicillin, macrolide, and cephalosporin resistant S. pneumoniae clinical isolates and cured mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate N-benzyl aminomethyl spectinomycins possess suitable properties for further development as novel antibacterial agents to treat drug resistant respiratory tract and sexually transmitted bacterial infections. |
| Databáze: | OpenAIRE |
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