title: A biocatalytic approach to capuramycin analogues by exploiting a substrate permissive N-transacylase CapW.
abstract: Using the ATP-independent transacylase CapW required for the biosynthesis of capuramycin-type antibiotics, we developed a biocatalytic approach for the synthesis of 43 analogues via a one-step aminolysis reaction from a methyl ester precursor as an acyl donor and various nonnative amines as acyl acceptors. Further examination of the donor substrate scope for CapW revealed that this enzyme can also catalyze a direct transamidation reaction using the major capuramycin congener as a semisynthetic precursor. Biological activity tests revealed that a few of the new capuramycin analogues have significantly improved antibiotic activity against Mycobacterium smegmatis MC2 155 and Mycobacterium tuberculosis H37Rv. Furthermore, most of the analogues are able to be covalently modified by the phosphotransferase CapP/Cpr17 involved in self resistance, providing critical insight for future studies regarding clinical development of the capuramycin antimycobacterial antibiotics.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA. svanlanen@uky.edu.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Jin
authors.forename: Wenlong
authors.initials: W
authors.lastname: Cai
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.forename: Anwesha
authors.initials: A
authors.lastname: Goswami
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
authors.forename: Koichi
authors.initials: K
authors.lastname: Nonaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Baba
authors.forename: Masanori
authors.initials: M
authors.lastname: Funabashi
authors.forename: Zhaoyong
authors.initials: Z
authors.lastname: Yang
authors.forename: Steven G
authors.initials: SG
authors.lastname: Van Lanen
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D000617:Aminoglycosides / Q000737:chemistry* / Q000494:pharmacology; D055162:Biocatalysis; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects; D013379:Substrate Specificity
chemical_list: D000617:Aminoglycosides; C049983:capuramycin; D000217:Acyltransferases