Ropponen Henni-Karoliina, Diamanti Eleonora, Siemens Alexandra, Illarionov Boris, Haupenthal Jörg, Fischer Markus, Rottmann Matthias, Witschel Matthias, Hirsch Anna K H
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI) Campus Building E8.1 66123 Saarbrücken Germany
Department of Pharmacy, Saarland University Campus Building E8.1 66123 Saarbrücken Germany.
RSC Med Chem. 2021 Mar 3;12(4):593-601. doi: 10.1039/d0md00409j. eCollection 2021 Apr 28.
In the search for new antibacterial compounds, we repositioned an antimalarial compound class by derivatising it based on the so-called "eNTRy" rules for enhanced accumulation into Gram-negative bacteria. We designed, synthesised and evaluated a small library of amino acid modified compounds together with the respective Boc-protected analogues, leading to no substantial improvement in antibacterial activity against wild-type K12, whereas more distinct activity differences were observed in mutant strains Δ, D22, Δ and BL21(DE3)omp8. A comparison of the activity results of the mutants with respect to the known rules related to enhanced activity against Gram-negative bacteria revealed that applicability of the rules is not always ensured. Out of the four amino acids used in this study, glycine derivatives showed highest antibacterial activity, although still suffering from efflux issues.
在寻找新型抗菌化合物的过程中，我们通过基于所谓的“eNTRy”规则对一种抗疟化合物类别进行衍生化，以使其增强在革兰氏阴性菌中的积累，从而对其进行了重新定位。我们设计、合成并评估了一个由氨基酸修饰化合物及其相应的Boc保护类似物组成的小型文库，结果显示对野生型K12的抗菌活性没有实质性提高，而在突变菌株Δ、D22、Δ和BL21(DE3)omp8中观察到了更明显的活性差异。将突变体的活性结果与已知的与增强对革兰氏阴性菌活性相关的规则进行比较后发现，这些规则的适用性并非总能得到保证。在本研究中使用的四种氨基酸中，甘氨酸衍生物表现出最高的抗菌活性，尽管仍存在外排问题。
