Stalobacin: Discovery of Novel Lipopeptide Antibiotics with Potent Antibacterial Activity against Multidrug-Resistant Bacteria

A novel lipopeptide antibiotic, stalobacin I (1), was discovered from a culture broth of an unidentified Gram-negative bacterium. Stalobacin I (1) had a unique chemical architecture composed of an upper and a lower half peptide sequence, which were linked via a hemiaminal methylene moiety. The sequence of 1 contained an unusual amino acid, carnosadine, 3,4-dihydroxyariginine, 3-hydroxyisoleucine, and 3-hydroxyaspartic acid, and a novel cyclopropyl fatty acid. The antibacterial activity of 1 against a broad range of drug-resistant Gram-positive bacteria was much stronger than those of “last resort” antibiotics such as vancomycin, linezolid, and telavancin (MIC 0.004–0.016 μg/mL). Furthermore, compound 1 induced a characteristic morphological change in Gram-positive and Gram-negative strains by inflating the bacterial cell body. The absolute configuration of a cyclopropyl amino acid, carnosadine, was determined by the synthetic study of its stereoisomers, which was an essential component for the strong activity of 1.本研究从一株未鉴定的革兰氏阴性菌（Gram-negative bacterium）的培养液中，分离得到一种新型脂肽抗生素stalobacin I（1）。该化合物具有独特的分子结构：由上下两段肽序列组成，两段序列通过半胺醛亚甲基（hemiaminal methylene）单元连接。其肽序列中包含稀有氨基酸carnosadine、3,4-二羟基精氨酸（3,4-dihydroxyarginine，原文为3,4-dihydroxyariginine，疑为拼写笔误）、3-羟基异亮氨酸（3-hydroxyisoleucine）、3-羟基天冬氨酸（3-hydroxyaspartic acid），以及一种新型环丙基脂肪酸（cyclopropyl fatty acid）。该化合物对多种耐药革兰氏阳性菌的抗菌活性远优于万古霉素（vancomycin）、利奈唑胺（linezolid）、特拉万星（telavancin）等“最后一线”抗生素，其最低抑菌浓度（MIC, Minimum Inhibitory Concentration）范围为0.004~0.016 μg/mL。此外，化合物1可通过使细菌菌体膨大，在革兰氏阳性菌与革兰氏阴性菌菌株中诱导出特征性形态变化。通过对其立体异构体的合成研究，确定了作为核心组成的环丙基氨基酸carnosadine的绝对构型，该构型是化合物1发挥强效抗菌活性的必要条件。