美国哈佛大学Daniel Kahne团队在研究中取得进展。他们发现，简单的仲胺通过与苯丙胺酸tRNA合成酶的高选择性结合抑制革兰氏阴性菌生长。 相关论文于2021年1月7日发表于《美国化学会志》。

利用基于细胞的筛选，研究组发现了一个简单的二级胺，可以抑制野生大肠杆菌和鲍氏不动杆菌的生长，但不影响革兰氏阳性生物枯草杆菌的生长。大肠杆菌和鲍氏不动杆菌中耐药性突变专门体现在胺酰-tRNA合成酶PheRS。

课题组研究人员证实了在生物化学上化合物抑制了这些生物中的PheRS，并表现出对枯草杆菌或人的PheRS不抑制。结构表明，化合物的苄基模拟了苯丙氨酸上的苄基。另一个胺取代基，2-(1-环己烯基)乙基基团，在其结合处诱导了一个疏水口袋。

通过生物信息学分析和突变，该课题组展示了，这个极度简单分子结构诱导产生一个互补口袋从而提供第二个取代基的能力，解释了其对革兰氏阴性PheRS的高选择性。由于这个二级胺结构针对野生革兰氏阴性病菌有活性但是对哺乳细胞没有细胞毒性，研究人员认为它有可能被开发用于联合抗生素疗法治疗革兰氏阴性菌感染。

据悉，抗生素治疗耐药革兰氏阴性菌感染面临迫切需求但是其研发具有挑战性。

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