Aminomethyl Spectinomycins as Novel Therapeutics for Drug Resistant Respiratory Tract and Sexually Transmitted Bacterial Infections

• Published in: Science translational medicine 2015-05, Vol.7 (288), p.288ra75-288ra75
• Main Authors: Bruhn, David F., Waidyarachchi, Samanthi L., Madhura, Dora B., Shcherbakov, Dimitri, Zheng, Zhong, Liu, Jiuyu, Abdelrahman, Yasser M., Singh, Aman P., Duscha, Stefan, Rathi, Chetan, Lee, Robin B., Belland, Robert J., Meibohm, Bernd, Rosch, Jason W., Böttger, Erik C., Lee, Richard E.
• Format: Article
• Language: English
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.3010572

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.