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

Abstract

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.

Structure–Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions

“…4 This is driven by the spectinomycin core rather than the spectinamide sidechain, with exposures similar to aminoglycoside antibiotics. 16 …”

“…13–15 Utilizing these early drug discovery studies and our modern knowledge of the molecular interaction of spectinomycin with the bacterial ribosome, 6 we have been able to generate two chemically distinct series of spectinomycins: spectinamides with narrow spectrum activity against M. tuberculosis ; 4 and the aminomethyl spectinomycins active against a broader range of respiratory tract and sexually transmitted bacterial pathogens. 16 …”

SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis

“…SP is a natural product aminocyclitol produced by Streptomyces spectabilis. It is a potent inhibitor of bacterial ribosomes and is accepted as therapeutic for respiratory tract and sexually transmitted infections 56 with an excellent safety profile 57 . GA, also known as anacardic acids, is a botanical drug isolated from the seed coat of Ginkgo biloba L. with a wide range of bioactive properties, including anti-bacterium, anti-HIV, and molluscicidal activities.…”

Structural recognition of spectinomycin by resistance enzyme ANT(9) fromEnterococcus faecalis

“…Lately, however, semi-synthetic modifications to spectinomycin, spectinamides and aminomethyl spectinomycins, have been proposed for treatment of multi-drug resistant tuberculosis and other infections (19,21). In these molecules, added functional groups on the 4-O position of the C-ring of spectinomycin mediate additional contacts in the spectinomycin-binding site of the ribosome and importantly, prevent the drug from being exported by the intrinsic efflux pump of M. tuberculosis.…”