Brunicardi Jackson E H, Small Jeramiah J, Padilla Maria Sophia Teresa Lee, Carrera Plancarte Jovanna I, Nowick James S
Department of Chemistry, University of California─Irvine, Irvine, California 92697, United States.
Department of Molecular Biology and Biochemistry, University of California─Irvine, Irvine, California 92697, United States.
J Org Chem. 2025 Feb 7;90(5):2132-2136. doi: 10.1021/acs.joc.4c02828. Epub 2025 Jan 26.
This paper reports highly active analogues of clovibactin in which the rare, noncanonical amino acid d-hydroxyasparagine is replaced with the commercially available amino acid d-threonine. Sequential mutation of leucines 2, 7, and 8 to the more hydrophobic homologue cyclohexylalanine dramatically increases the antibiotic activity of d-Thr-clovibactin. The resulting analogues (d-Cha,d-Thr-clovibactin, Cha,d-Thr-clovibactin, and Cha,d-Thr-clovibactin) are readily prepared by standard peptide synthesis techniques and exhibit excellent activity (≤1 μg/mL) against the Gram-positive, drug-resistant pathogens MRSA and VRE.
本文报道了氯缬菌素的高活性类似物，其中罕见的非标准氨基酸d-羟基天冬酰胺被市售氨基酸d-苏氨酸所取代。将第2、7和8位的亮氨酸依次突变为疏水性更强的同系物环己基丙氨酸，可显著提高d-苏氨酸-氯缬菌素的抗生素活性。通过标准肽合成技术可轻松制备得到所得类似物（d-环己基丙氨酸，d-苏氨酸-氯缬菌素、环己基丙氨酸，d-苏氨酸-氯缬菌素和环己基丙氨酸，d-苏氨酸-氯缬菌素），它们对革兰氏阳性耐药病原体耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素肠球菌（VRE）表现出优异的活性（≤1 μg/mL）。
