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
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
Sci Transl Med. 2015 May 20;7(288):288ra75. 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 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.
抗生素壮观霉素是一种强效的细菌蛋白质合成抑制剂，具有独特的作用机制和出色的安全指数，但对大多数临床上重要的病原体缺乏抗菌活性。基于对氨甲基壮观霉素结合位点的计算分析和结构导向合成，开发了一系列N-苄基取代的3'-(R)-3'-氨甲基-3'-羟基壮观霉素。这些化合物的核糖体抑制值与壮观霉素相当，但对常见呼吸道病原体肺炎链球菌、流感嗜血杆菌、嗜肺军团菌和卡他莫拉菌，以及性传播细菌淋病奈瑟菌和沙眼衣原体的效力有所增强。先导化合物的非核糖体结合3'-(S)异构体在体外蛋白质翻译试验中表现出较弱的抑制活性，抗菌活性较差，这表明该系列化合物的抗菌活性仍然靶向核糖体。化合物在大鼠中还表现出无哺乳动物细胞毒性、微粒体稳定性提高和良好的药代动力学性质。该系列中的先导化合物表现出优于壮观霉素的出色化学稳定性；与一组人类受体和药物代谢酶无相互作用，表明体内不良反应或药物-药物相互作用的可能性较低；对一组耐青霉素、大环内酯和头孢菌素的肺炎链球菌临床分离株具有体外活性；并且能够以5mg/kg的剂量治愈致命性肺炎球菌肺炎和败血症的小鼠。总之，这些研究表明N-苄基氨甲基壮观霉素适合进一步开发用于治疗耐药性呼吸道和性传播细菌感染。
