Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India.
Molecular Biophysics Unit (MBU), Indian Institute of Science, Bangalore 560012, India.
Sci Adv. 2019 Jul 24;5(7):eaax1946. doi: 10.1126/sciadv.aax1946. eCollection 2019 Jul.
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 (Ω76) displayed high efficacy against carbapenem and tigecycline-resistant in mice. Mice treated with repeated sublethal doses of Ω76 displayed no signs of chronic toxicity. Sublethal Ω76 doses co-administered alongside sublethal colistin doses displayed no additive toxicity. These results indicate that Ω76 can potentially supplement or replace colistin, especially where nephrotoxicity is a concern. To our knowledge, no other existing antibiotics occupy this clinical niche. Mechanistically, Ω76 adopts an α-helical structure in membranes, causing rapid membrane disruption, leakage, and bacterial death.
耐药性是一个公共卫生关注点，有可能破坏几十年来的医学进展。ESKAPE 病原体导致大多数医院获得性感染，并且经常对碳青霉烯类抗生素具有耐药性，通常使替加环素和黏菌素成为最后的治疗选择。然而，替加环素耐药性的增加和黏菌素的肾毒性严重限制了这些抗生素的使用。我们使用最大公共子图方法设计了抗菌肽。我们最好的肽（Ω76）在小鼠中对碳青霉烯类和替加环素耐药菌显示出很高的疗效。用重复亚致死剂量的 Ω76 治疗的小鼠没有显示出慢性毒性的迹象。与亚致死剂量的黏菌素联合使用的亚致死剂量的 Ω76 没有显示出附加毒性。这些结果表明，Ω76 有可能补充或替代黏菌素，特别是在肾毒性是一个问题的情况下。据我们所知，没有其他现有的抗生素占据这一临床利基。从机制上讲，Ω76 在膜中采用α-螺旋结构，导致快速的膜破坏、渗漏和细菌死亡。
