Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides
Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides
复制标题
针对病原菌中甲硫氨酸氨肽酶的自源结构破坏肽：产生抗菌肽的新策略
DOI：
10.1096/fj.201700613rr
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Zhou Yaoqi
中科院分区：
文献类型：
--
作者：
Zhan Jian;Jia Husen;Semchenko Evgeny A.;Bian Yunqiang;Zhou Amy M.;Li Zhixiu;Yang Yuedong;Wang Jihua;Sarkar Sohinee;Totsika Makrina;Blanchard Helen;Jen Freda E. -C.;Ye Qizhuang;Haselhorst Thomas;Jennings Michael P.;Seib Kate L.;Zhou Yaoqi
细菌感染是年轻人、老年人和免疫功能低下患者死亡的主要原因之一。多重耐药（MDR）细菌的快速传播是全球卫生紧急情况，缺乏控制MDR病原体的新药。我们描述了一个迄今为止未探索的发现新抗生素的途径，是基于自我靶向，结构破坏肽。我们表明，螺旋肽，KFF-EcH 3，来自大肠杆菌甲硫氨酸氨肽酶可以破坏这种必需的酶的二级和三级结构，从而杀死细菌（包括MDR菌株）。值得注意的是，没有针对这种肽产生可检测到的耐药性。基于计算分析，我们的研究预测，肽KFF-EcH 3与甲硫氨酸氨肽酶的结构核心具有最强的相互作用。我们进一步使用我们的方法来鉴定肽KFF-NgH 1以靶向来自淋病奈瑟菌的相同酶。这种肽抑制细菌生长，并能够在人宫颈上皮细胞模型中治疗淋球菌感染。这些发现为抗生素发现提供了一个令人兴奋的新范例，使用自衍生肽，可以开发用于靶向任何必需细菌蛋白的结构。詹，J.，贾，H.，Semchenko，E.一、卞，Y.，Zhou，中国古柏A. M.，Li，Z.，杨，Y.，王杰，萨卡尔，S.，Totsika，M.，布兰查德，H.，Jen，F. E.- C.的方法，叶，Q.，Haselhorst，T.，Jennings，M. P.，Seib，K. L.，Zhou，Y.以致病菌甲硫氨酸氨肽酶为靶点的自衍生结构破坏肽：产生抗菌肽的新策略。
Bacterial infection is one of the leading causes of death in young, elderly, and immune-compromised patients. The rapid spread of multi-drug–resistant (MDR) bacteria is a global health emergency and there is a lack of new drugs to control MDR pathogens. We describe a heretofore-unexplored discovery pathway for novel antibiotics that is based on self-targeting, structure-disrupting peptides. We show that a helical peptide, KFF-EcH3, derived from the Escherichia coli methionine aminopeptidase can disrupt secondary and tertiary structure of this essential enzyme, thereby killing the bacterium (including MDR strains). Significantly, no detectable resistance developed against this peptide. Based on a computational analysis, our study predicted that peptide KFF-EcH3 has the strongest interaction with the structural core of the methionine aminopeptidase. We further used our approach to identify peptide KFF-NgH1 to target the same enzyme from Neisseria gonorrhoeae. This peptide inhibited bacterial growth and was able to treat a gonococcal infection in a human cervical epithelial cell model. These findings present an exciting new paradigm in antibiotic discovery using self-derived peptides that can be developed to target the structures of any essential bacterial proteins.—Zhan, J., Jia, H., Semchenko, E. A., Bian, Y., Zhou, A. M., Li, Z., Yang, Y., Wang, J., Sarkar, S., Totsika, M., Blanchard, H., Jen, F. E.-C., Ye, Q., Haselhorst, T., Jennings, M. P., Seib, K. L., Zhou, Y. Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides.