仲胺通過與苯丙氨酸tRNA合成酶的高選擇性結合抑制革蘭氏陰性菌的生長
作者：
小柯機器人發布時間：2021/1/10 19:37:35
美國哈佛大學Daniel Kahne團隊在研究中取得進展。他們發現，簡單的仲胺通過與苯丙胺酸tRNA合成酶的高選擇性結合抑制革蘭氏陰性菌生長。 相關論文於2021年1月7日發表於《美國化學會志》。
利用基於細胞的篩選，研究組發現了一個簡單的二級胺，可以抑制野生大腸桿菌和鮑氏不動桿菌的生長，但不影響革蘭氏陽性生物枯草桿菌的生長。大腸桿菌和鮑氏不動桿菌中耐藥性突變專門體現在胺醯-tRNA合成酶PheRS。
課題組研究人員證實了在生物化學上化合物抑制了這些生物中的PheRS，並表現出對枯草桿菌或人的PheRS不抑制。結構表明，化合物的苄基模擬了苯丙氨酸上的苄基。另一個胺取代基，2-(1-環己烯基)乙基基團，在其結合處誘導了一個疏水口袋。
通過生物信息學分析和突變，該課題組展示了，這個極度簡單分子結構誘導產生一個互補口袋從而提供第二個取代基的能力，解釋了其對革蘭氏陰性PheRS的高選擇性。由於這個二級胺結構針對野生革蘭氏陰性病菌有活性但是對哺乳細胞沒有細胞毒性，研究人員認為它有可能被開發用於聯合抗生素療法治療革蘭氏陰性菌感染。
據悉，抗生素治療耐藥革蘭氏陰性菌感染面臨迫切需求但是其研發具有挑戰性。
附：英文原文
Title: Simple Secondary Amines Inhibit Growth of Gram-Negative Bacteria through Highly Selective Binding to Phenylalanyl-tRNA Synthetase
Author: Vadim Baidin, Tristan W. Owens, Michael B. Lazarus, Daniel Kahne
Issue&Volume: January 7, 2021
Abstract: Antibiotics to treat drug-resistant Gram-negative infections are urgently needed but challenging to discover. Using a cell-based screen, we identified a simple secondary amine that inhibited the growth of wild-type Escherichia coli and Acinetobacter baumannii but not the growth of the Gram-positive organism Bacillus subtilis. Resistance mutations in E. coli and A. baumannii mapped exclusively to the aminoacyl-tRNA synthetase PheRS. We confirmed biochemically that the compound inhibited PheRS from these organisms and showed that it did not inhibit PheRS from B. subtilis or humans. To understand the basis for the compound’s high selectivity for only some PheRS enzymes, we solved crystal structures of E. coli and A. baumannii PheRS complexed with the inhibitor. The structures showed that the compound’s benzyl group mimics the benzyl of phenylalanine. The other amine substituent, a 2-(cyclohexen-1-yl)ethyl group, induces a hydrophobic pocket in which it binds. Through bioinformatic analysis and mutagenesis, we show that the ability to induce a complementary hydrophobic pocket that can accommodate the second substituent explains the high selectivity of this remarkably simple molecular scaffold for Gram-negative PheRS. Because this secondary amine scaffold is active against wild-type Gram-negative pathogens but is not cytotoxic to mammalian cells, we suggest that it may be possible to develop it for use in combination antibiotic therapy to treat Gram-negative infections.
DOI: 10.1021/jacs.0c11113
Source: https://pubs.acs.org/doi/10.1021/jacs.0c11113