Ω76: A designed antimicrobial peptide to combat carbapenem- and tigecycline-resistant Acinetobacter baumannii
Ω76: A designed antimicrobial peptide to combat carbapenem- and tigecycline-resistant Acinetobacter baumannii
复制标题
DOI：
10.1126/sciadv.aax1946
复制
发表时间：
2019-07-01
期刊：
影响因子：
13.6
通讯作者：
Chandra, Nagasuma
中科院分区：
文献类型：
--
作者：
Nagarajan, Deepesh;Roy, Natasha;Chandra, Nagasuma
耐药性是一个公共卫生问题，可能会破坏数十年的医学进步。ESKAPE病原体引起大多数医院感染，并且经常对碳青霉烯类抗生素耐药，通常将替加环素和粘菌素作为最后的治疗选择。然而，增加替加环素耐药性和粘菌素的肾毒性严重限制了这些抗生素的使用。我们设计了抗菌肽使用最大公共子图的方法。我们最好的肽（Omega 76）在小鼠中对碳青霉烯类和替加替林耐药鲍曼不动杆菌显示出高疗效。用重复亚致死剂量的Omega 76处理的小鼠没有显示出慢性毒性的迹象。亚致死Omega 76剂量与亚致死粘菌素剂量共同给药未显示出累加毒性。这些结果表明，欧米茄76可以潜在地补充或替代粘菌素，特别是在肾毒性是一个问题。据我们所知，没有其他现有的抗生素占据这个临床利基。在机械上，Omega 76在膜中采用α-螺旋结构，导致膜快速破裂，泄漏和细菌死亡。
Drug resistance is a public health concern that threatens to undermine decades of medical progress. ESKAPE pathogens cause most nosocomial infections, and are frequently resistant to carbapenem antibiotics, usually leaving tigecycline and colistin as the last treatment options. However, increasing tigecycline resistance and colistin's nephrotoxicity severely restrict use of these antibiotics. We have designed antimicrobial peptides using a maximum common subgraph approach. Our best peptide (Omega 76) displayed high efficacy against carbapenem and tigecycline-resistant Acinetobacter baumannii in mice. Mice treated with repeated sublethal doses of Omega 76 displayed no signs of chronic toxicity. Sublethal Omega 76 doses co-administered alongside sublethal colistin doses displayed no additive toxicity. These results indicate that Omega 76 can potentially supplement or replace colistin, especially where nephrotoxicity is a concern. To our knowledge, no other existing antibiotics occupy this clinical niche. Mechanistically, Omega 76 adopts an a-helical structure in membranes, causing rapid membrane disruption, leakage, and bacterial death.