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Publication Abstract from PubMed

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 Clostridioides difficile. In the course of these studies, we found that the cytochrome P450 enzyme OxyB(ker) 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(ker), determined to 2.8 A, points to structural features that may contribute to these properties. Our results set the stage for using OxyB(ker) broadly as a biocatalyst toward the chemoenzymatic synthesis of diverse GPA analogues.

Robust Chemoenzymatic Synthesis of Keratinimicin Aglycone Analogues Facilitated by the Structure and Selectivity of OxyB.,Hauser N, Ireland KA, Chioti VT, Forneris CC, Davis KM, Seyedsayamdost MR ACS Chem Biol. 2023 Jul 21;18(7):1473-1479. doi: 10.1021/acschembio.3c00192. Epub , 2023 Jul 5. PMID:37405871^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.