Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections.
Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections.
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DOI：
10.1126/scitranslmed.3010572
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发表时间：
2015-05-20
影响因子：
17.1
通讯作者：
Lee RE
中科院分区：
文献类型：
--
作者：
Bruhn DF;Waidyarachchi SL;Madhura DB;Shcherbakov D;Zheng Z;Liu J;Abdelrahman YM;Singh AP;Duscha S;Rathi C;Lee RB;Belland RJ;Meibohm B;Rosch JW;Böttger EC;Lee RE
抗生素大观霉素是一种有效的细菌蛋白质合成抑制剂，具有独特的作用机制和优异的安全指数，但它缺乏对大多数临床重要病原体的抗菌活性。基于氨甲基大观霉素结合位点的计算分析和结构导向合成，合成了一系列N-苄基取代的3 '-（R）-3'-氨甲基-3 '-羟基大观霉素。这些化合物的核糖体抑制值与大观霉素相当，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增加。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测定中表现出弱的抑制活性和差的抗菌活性，表明该系列的抗菌活性保持在靶标上。除了改进的抗菌效力之外，化合物还在大鼠中显示出无哺乳动物细胞毒性、改进的微粒体稳定性和有利的药代动力学性质。来自该系列的先导化合物化合物1表现出优异的化学稳定性，其上级于壮观霉素，并且与一组人受体和药物代谢酶没有显著的相互作用，表明体内不良反应或药物-药物相互作用的可能性低。化合物1在体外对一组青霉素、大环内酯和头孢菌素耐药的沙门氏菌有活性。pneumoniae临床分离株和治愈小鼠的致死性肺炎球菌肺炎和败血症。总之，这些研究表明N-苄基氨甲基壮观霉素具有进一步开发为新型抗菌剂以治疗耐药性呼吸道和性传播细菌感染的合适特性。
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.