Department of Chemistry, University of California─Irvine, Irvine, California 92697, United States.
Department of Pharmaceutical Sciences, University of California─Irvine, Irvine, California 92697, United States.
J Org Chem. 2024 Oct 18;89(20):15325-15330. doi: 10.1021/acs.joc.4c01674. Epub 2024 Sep 30.
The unusual d-l-l-d-d-l-l pattern of stereochemistry in residues 1-7 of the peptide antibiotic teixobactin is critical to its extraordinary antibiotic activity, creating an unusual amphiphilic β-sheetlike structure that is essential to its mechanism of action. The current study sought to replace the three d-amino acids in the tail with l-amino acids while maintaining amphiphilicity. We find that swapping residues d-Gln and d--Ile in -acyl isopeptide prodrugs of teixobactin permits the introduction of l-stereochemistry with retention of antibiotic activity. Nevertheless, modifying the -terminal stereochemistry results in a loss of antibiotic activity.
肽类抗生素泰妙菌素残基 1-7 中立体化学的不寻常 d-l-d-d-l-l 模式对其非凡的抗生素活性至关重要，形成了一种不寻常的两亲性 β-折叠样结构，这是其作用机制的关键。本研究试图在保持两亲性的同时，用 l-氨基酸取代尾部的三个 d-氨基酸。我们发现，在泰妙菌素的酰基异肽前药中替换残基 d-Gln 和 d-Ile，允许引入 l-立体化学，同时保留抗生素活性。然而，修饰 -末端立体化学会导致抗生素活性丧失。
