Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States.
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.
ACS Chem Biol. 2023 Jul 21;18(7):1473-1479. doi: 10.1021/acschembio.3c00192. Epub 2023 Jul 5.
The emergence of multidrug-resistant pathogens poses a threat to public health and requires new antimicrobial agents. As the archetypal glycopeptide antibiotic (GPA) used against drug-resistant Gram-positive pathogens, vancomycin provides a promising starting point. Peripheral alterations to the vancomycin scaffold have enabled the development of new GPAs. However, modifying the core remains challenging due to the size and complexity of this compound family. The recent successful chemoenzymatic synthesis of vancomycin suggests that such an approach can be broadly applied. Herein, we describe the expansion of chemoenzymatic strategies to encompass type II GPAs bearing all aromatic amino acids through the production of the aglycone analogue of keratinimicin A, a GPA that is 5-fold more potent than vancomycin against . In the course of these studies, we found that the cytochrome P450 enzyme OxyB boasts both broad substrate tolerance and remarkable selectivity in the formation of the first aryl ether cross-link on the linear peptide precursors. The X-ray crystal structure of OxyB, determined to 2.8 Å, points to structural features that may contribute to these properties. Our results set the stage for using OxyB broadly as a biocatalyst toward the chemoenzymatic synthesis of diverse GPA analogues.
多药耐药病原体的出现对公共健康构成了威胁，需要新的抗菌药物。万古霉素作为用于治疗耐药革兰氏阳性病原体的典型糖肽抗生素 (GPA)，为我们提供了一个有希望的起点。对万古霉素支架进行外围修饰，使新型 GPA 得以开发。然而，由于该化合物家族的庞大和复杂，对其核心进行修饰仍然具有挑战性。最近，万古霉素的成功化学酶合成表明，这种方法可以广泛应用。在此，我们描述了扩大化学酶策略的范围，通过生产角蛋白霉素 A 的糖苷类似物来涵盖具有所有芳香族氨基酸的 II 型 GPA，该 GPA 对 的活性比万古霉素高 5 倍。在这些研究过程中，我们发现细胞色素 P450 酶 OxyB 在形成线性肽前体上的第一个芳基醚交联时具有广泛的底物耐受性和显著的选择性。OxyB 的 X 射线晶体结构确定为 2.8 Å，表明结构特征可能有助于这些特性。我们的结果为广泛使用 OxyB 作为生物催化剂，通过化学酶合成各种 GPA 类似物奠定了基础。
