Compound Uptake into E. coli Can Be Facilitated by N-Alkyl Guanidiniums and Pyridiniums.
Compound Uptake into E. coli Can Be Facilitated by N-Alkyl Guanidiniums and Pyridiniums.
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DOI：
10.1021/acsinfecdis.0c00715
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发表时间：
2021-01-08
影响因子：
5.3
通讯作者：
Hergenrother PJ
中科院分区：
文献类型：
--
作者：
Perlmutter SJ;Geddes EJ;Drown BS;Motika SE;Lee MR;Hergenrother PJ
多重耐药革兰氏阴性细菌感染正在上升，并且在50多年来没有FDA批准新类别的广谱抗生素，这些感染对人类健康构成重大威胁。一个重大的挑战是大多数化合物不能在革兰氏阴性菌中积累。最近开发的预测指南表明，将伯胺附加到适当形状的化合物上可以增强革兰氏阴性菌的积累。在这里，我们报告说，其他带正电荷的氮官能团，即，N-烷基胍和吡啶，也可以促进化合物吸收到革兰氏阴性细菌。在大肠杆菌中评估了一组60种非抗生素化合物（由20种伯胺及其相应的胍和吡啶组成）的累积。我们还将这些替代官能团安装到抗生素支架上，并评估它们在革兰氏阴性菌中的积累和抗菌活性。结果表明，当设计具有革兰氏阴性活性的抗生素时，应考虑其他带正电荷的含氮官能团。
Multidrug-resistant Gram-negative bacterial infections are on the rise, and with no FDA approvals for new classes of broad-spectrum antibiotics in over 50 years, these infections constitute a major threat to human health. A significant challenge is the inability of most compounds to accumulate in Gram-negative bacteria. Recently developed predictive guidelines show that appending a primary amine to an appropriately shaped compound can enhance Gram-negative accumulation. Here, we report that other positively charged nitrogen functional groups, namely, N-alkyl guanidiniums and pyridiniums, can also facilitate compound uptake into Gram-negative bacteria. The accumulation of a set of 60 nonantibiotic compounds, consisting of 20 primary amines and their corresponding guanidiniums and pyridiniums, was assessed in Escherichia coli. We also installed these alternate functional groups onto antibiotic scaffolds and assessed their accumulation and antibacterial activity in Gram-negative bacteria. The results suggest that other positively-charged, nitrogen-containing functional groups should be considered when designing antibiotics with Gram-negative activity.
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