Institute for Insect Biotechnology, Division for Natural Product Research, Justus-Liebig-University Giessen, Ohlebergsweg 12, 35392 Giessen, Germany; German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Ohlebergsweg 12, 35392 Giessen, Germany.
Institute for Insect Biotechnology, Division for Natural Product Research, Justus-Liebig-University Giessen, Ohlebergsweg 12, 35392 Giessen, Germany.
Cell Chem Biol. 2023 Aug 17;30(8):943-952.e7. doi: 10.1016/j.chembiol.2023.06.011. Epub 2023 Jul 13.
Darobactins represent a class of ribosomally synthesized and post-translationally modified peptide (RiPP) antibiotics featuring a rare bicyclic structure. They target the Bam-complex of Gram-negative bacteria and exhibit in vivo activity against drug-resistant pathogens. First isolated from Photorhabdus species, the corresponding biosynthetic gene clusters (BGCs) are widespread among γ-proteobacteria, including the genera Vibrio, Yersinia, and Pseudoalteromonas (P.). While the organization of the BGC core is highly conserved, a small subset of Pseudoalteromonas carries an extended BGC with additional genes. Here, we report the identification of brominated and dehydrated darobactin derivatives from P. luteoviolacea strains. The marine derivatives are active against multidrug-resistant (MDR) Gram-negative bacteria and showed solubility and plasma protein binding ability different from darobactin A, rendering it more active than darobactin A. The halogenation reaction is catalyzed by DarH, a new class of flavin-dependent halogenases with a novel fold.
达罗巴丁是一类核糖体合成和翻译后修饰的肽类（RiPP）抗生素，具有罕见的双环结构。它们靶向革兰氏阴性菌的 Bam 复合物，并在体内对耐药病原体表现出活性。达罗巴丁最初从 Photorhabdus 物种中分离出来，相应的生物合成基因簇（BGCs）广泛存在于γ-变形菌中，包括弧菌属、耶尔森氏菌属和假交替单胞菌属（P.）。虽然 BGC 核心的组织高度保守，但一小部分假交替单胞菌携带扩展的 BGC 和额外的基因。在这里，我们报道了从 P. luteoviolacea 菌株中鉴定出溴化和脱水达罗巴丁衍生物。海洋衍生物对多药耐药（MDR）革兰氏阴性菌具有活性，并且表现出与达罗巴丁 A 不同的溶解度和血浆蛋白结合能力，使其比达罗巴丁 A 更具活性。卤化反应由 DarH 催化，DarH 是一种具有新型折叠的新型黄素依赖性卤化酶。
