Identification and evaluation of improved 4'-O-(alkyl) 4,5-disubstituted 2-deoxystreptamines as next-generation aminoglycoside antibiotics.
Identification and evaluation of improved 4'-O-(alkyl) 4,5-disubstituted 2-deoxystreptamines as next-generation aminoglycoside antibiotics.
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改进的 4'-O-（烷基）4,5-二取代 2-脱氧链霉胺作为下一代氨基糖苷类抗生素的鉴定和评估。
DOI：
10.1128/mbio.01827-14
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发表时间：
2014-09-30
期刊：
影响因子：
6.4
通讯作者：
Böttger EC
中科院分区：
文献类型：
--
作者：
Duscha S;Boukari H;Shcherbakov D;Salian S;Silva S;Kendall A;Kato T;Akbergenov R;Perez-Fernandez D;Bernet B;Vaddi S;Thommes P;Schacht J;Crich D;Vasella A;Böttger EC
新出现的耐药性流行病使有效且安全的抗生素的开发成为当前研究的焦点。在这里，我们报告了下一代氨基糖苷类药物的设计。发现工作的驱动力是合理合成，重点是氨基糖苷类巴龙霉素的 4' 烷基化，目标是减轻氨基糖苷类最严重和致残的副作用——不可逆的听力损失。在体外核糖体翻译测定中评估化合物的目标活性、针对选定病原体的抗菌效力、针对哺乳动物细胞的细胞毒性以及体内耳毒性。这项研究的结果产生了有效的化合物，对核糖体靶标具有优异的选择性，具有良好的抗菌活性，并且长期给药时几乎没有耳毒性（如果有的话）。良好的生物相容性与有前景的抗菌活性相结合，强调了下一代氨基糖苷类药物在治疗传染病方面的潜力，且没有耳毒性的风险。多重耐药传染病的流行不断扩大，以及现代筛选平台中出现的新型抗菌药物的缺乏，要求对现有药物进行重新研究，重点是改善生物相容性和克服耐药机制。在这里，我们描述了已建立的氨基糖苷类抗生素巴龙霉素衍生物的制备和评估，这些衍生物有效地消除了其最大的缺陷——耳毒性，并克服了某些细菌耐药机制。
The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4′ alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides—irreversible hearing loss. Compounds were evaluated for target activity in in vitro ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and in vivo ototoxicity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity. The ever-widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms.