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Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections

A new series of spectinomycin analogs with potency against drug-resistant bacterial pathogens was designed and developed with a structure-based approach and validated in vitro and in vivo. Teaching an old antibiotic new tricks More and more cases of gonorrhea no longer respond to standard antibiotic treatment, leading the CDC (U.S. Centers for Disease Control and Prevention) to classify Neisseria gonorrhoeae as an urgent threat. New antibiotics are urgently needed to treat this and other emerging drug-resistant pathogens. To this end, Bruhn and Waidyarachchi et al. have taken a second look at an old group of antibiotics, the spectinomycins, a class of drugs that inhibit bacterial protein synthesis but do not kill many types of pathogens. By carefully mapping how the drug binds to the ribosome structure, the authors determined that N-benzyl–substituted spectinomycins should be able to inhibit the ribosomes of a broad spectrum of bacteria that produce disease. And indeed, this new series potently inhibited bacteria that cause respiratory illness (Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis) and sexually transmitted disease (N. gonorrhoeae and Chlamydia trachomatis). Their pharmacokinetics properties were promising, and assays showed that they are unlikely to cause adverse reactions. These new spectinomycins are active against drug-resistant forms of S. pneumoniae and cure mice of fatal pneumococcal pneumonia and sepsis, an encouraging result for the eventual use of these drugs for human infection. 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 series of N-benzyl–substituted 3′-(R)-3′-aminomethyl-3′-hydroxy spectinomycins was developed on the basis of 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 the 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 lead compounds 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 against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.